Patent Publication Number: US-2022235359-A1

Title: Nucleic acid, pharmaceutical composition, conjugate, preparation method, and use

Description:
TECHNICAL FIELD 
     The present disclosure relates to a nucleic acid capable of inhibiting expression of a xanthine oxidase (XO) gene, and a pharmaceutical composition and an siRNA conjugate containing the nucleic acid. The present disclosure also relates to a preparation method and use of the nucleic acid, the pharmaceutical composition and the siRNA conjugate. 
     BACKGROUND 
     Gout is a disease directly related to hyperuricemia caused by purine metabolism disorder and/or uric acid excretion decrease. Gout has been a common disease in developed countries such as Europe and America since ancient times. After the Second World War, with the economic development of various countries, the prevalence rate of gout has been increasing year by year in the world, and has been gradually increased with the trend of patients being young. At present, there are 12 million patients suffering from gout in China. 
     Xanthine oxidase (XO) is one of the key targets for treating gout. By inhibiting the expression of XO, the production of hypoxanthine and guanine can be effectively inhibited, and then the production of uric acid can be reduced, thus achieving the purpose of relieving the progress of gout and reversing the disease. By inhibiting the expression of the XO gene, diseases caused by abnormal uric acid metabolism, especially hyperuricemia and gout, can be prevented and treated at the cellular level. Small interfering RNA (siRNA), based on the mechanism of RNA interference (RNAi), can inhibit or block the expression of interested target genes in a sequence-specific way, thus achieving the purpose of treating diseases. 
     One of the keys to develop siRNA drugs for inhibiting the expression of the XO gene and treating the disease caused by the abnormal uric acid metabolism lies in finding a suitable siRNA and modification and an effective delivery system thereof. 
     SUMMARY OF THE INVENTION 
     The inventors of the present disclosure have surprisingly found that the following siRNA and modification sequence thereof provided by the present disclosure can specifically inhibit the expression of the XO gene, and the pharmaceutical composition or the siRNA conjugate can specifically target the liver, thereby inhibiting the expression of the XO gene in the liver and realizing the treatment or prevention of the disease caused by the abnormal uric acid metabolism, thus completing the present disclosure. 
     In some embodiments, the present disclosure provides an siRNA capable of inhibiting expression of an XO gene. The siRNA comprises a sense strand and an antisense strand, each nucleotide in the siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a nucleotide sequence I, and the antisense strand comprises a nucleotide sequence II; the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region; and the nucleotide sequence I and the nucleotide sequence II are selected from a group of sequences shown in the following i)-xii): 
     i) the nucleotide sequence I has the same length and no more than three nucleotides difference from the nucleotide sequence shown in SEQ ID NO: 1; and the nucleotide sequence II has the same length and no more than three nucleotides difference from the nucleotide sequence shown in SEQ ID NO: 2: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 1) 
               
               
                   
                 5&#39;-GAGAUGAAGUUCAAGAAUZ 1 -3&#39;; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 2) 
               
               
                   
                 5&#39;-Z 2 AUUCUUGAACUUCAUCUC-3&#39;, 
               
            
           
         
       
     
     wherein, Z 1  is A, Z 2  is U, the nucleotide sequence I comprises a nucleotide Z 3  at a corresponding site to Z 1 , the nucleotide sequence II comprises a nucleotide Z 4  at a corresponding site to Z 2 , and Z 4  is the first nucleotide from the 5′ terminal of the antisense strand; 
     ii) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 61; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 62: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 61) 
               
               
                   
                 5&#39;-CAUAACUGGAAUUUGUAAZ 5 -3&#39;; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 62) 
               
               
                   
                 5&#39;-Z 6 UUACAAAUUCCAGUUAUG-3&#39;, 
               
            
           
         
       
     
     wherein, Z 5  is U, Z 6  is A, the nucleotide sequence I comprises a nucleotide Z 7  at a corresponding site to Z 5 , the nucleotide sequence II comprises a nucleotide Z 8  at a corresponding site to Z 6 , and Z 8  is the first nucleotide from the 5′ terminal of the antisense strand; 
     iii) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 121; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 122: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 121) 
               
               
                   
                 5&#39;-CAUUAUCACAAUUGAGGAZ 9 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 122) 
               
               
                   
                 5′-Z 10 UCCUCAAUUGUGAUAAUG-3′, 
               
            
           
         
       
     
     wherein, Z 9  is U, Z 10  is A, the nucleotide sequence I comprises a nucleotide Z 11  at a corresponding site to Z 9 , the nucleotide sequence II comprises a nucleotide Z 12  at a corresponding site to Z 10 , and Z 12  is the first nucleotide from the 5′ terminal of the antisense strand; 
     iv) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 181; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 182: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 181) 
               
               
                   
                 5′-GGAUCUCUCUCAGAGUAUZ 13 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 182) 
               
               
                   
                 5′-Z 14 AUACUCUGAGAGAGAUCC-3′, 
               
            
           
         
       
     
     wherein, Z 13  is U, Z 14  is A, the nucleotide sequence I comprises a nucleotide Z 15  at a corresponding site to Z 13 , the nucleotide sequence II comprises a nucleotide Z 16  at a corresponding site to Z 14 , and Z 16  is the first nucleotide from the 5′ terminal of the antisense strand; 
     v) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 241; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 242: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 241) 
               
               
                   
                 5′-ACAUGGACAACUGCUAUAZ 17 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 242) 
               
               
                   
                 5′-Z 18 UAUAGCAGUUGUCCAUGU-3′, 
               
            
           
         
       
     
     wherein, Z 17  is A, Z 18  is U, the nucleotide sequence I comprises a nucleotide Z 19  at a corresponding site to Z 17 , the nucleotide sequence II comprises a nucleotide Z 20  at a corresponding site to Z 18 , and Z 20  is the first nucleotide from the 5′ terminal of the antisense strand; 
     vi) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 301; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 302: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 301) 
               
               
                   
                 5′-UAGCAAGCUCUCAGUAUCZ 21 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 302) 
               
               
                   
                 5′-Z 22 GAUACUGAGAGCUUGCUA-3′, 
               
            
           
         
       
     
     wherein, Z 21  is A, Z 22  is U, the nucleotide sequence I comprises a nucleotide Z 23  at a corresponding site to Z 21 , the nucleotide sequence II comprises a nucleotide Z 24  at a corresponding site to Z 22 , and Z 24  is the first nucleotide from the 5′ terminal of the antisense strand; 
     vii) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 361; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 362: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 361) 
               
               
                   
                 5′-AUAAGGUUACUUGUGUUGZ 25 -3′; 
               
               
                   
                   
               
               
                   
                 5′-Z 26 CAACACAAGUAACCUUAU-3′, 
               
               
                   
                 (SEQ ID NO: 362) 
               
            
           
         
       
     
     wherein, Z 25  is Z 26  is C, the nucleotide sequence I comprises a nucleotide Z 27  at a corresponding site to Z 25 , the nucleotide sequence II comprises a nucleotide Z 28  at a corresponding site to Z 26 , and Z 28  is the first nucleotide from the 5′ terminal of the antisense strand; 
     viii) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 421; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 422: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 421) 
               
               
                   
                 5′-GAAAAUCACCUAUGAAGAZ 29 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 422) 
               
               
                   
                 5′-Z 30 UCUUCAUAGGUGAUUUUC-3′, 
               
            
           
         
       
     
     wherein, Z 29  is A, Z 30  is U, the nucleotide sequence I comprises a nucleotide Z 31  at a corresponding site to Z 29 , the nucleotide sequence II comprises a nucleotide Z 32  at a corresponding site to Z 30 , and Z 32  is the first nucleotide from the 5′ terminal of the antisense strand; 
     ix) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 481; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 482: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 481) 
               
               
                   
                 5′-GAUGCUAUAAAGAACAACZ 33 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 482) 
               
               
                   
                 5′-Z 34 GUUGUUCUUUAUAGCAUC-3′, 
               
            
           
         
       
     
     wherein, Z 33  is U, Z 34  is A, the nucleotide sequence I comprises a nucleotide Z 35  at a corresponding site to Z 33 , the nucleotide sequence II comprises a nucleotide Z 36  at a corresponding site to Z 34 , and Z 36  is the first nucleotide from the 5′ terminal of the antisense strand; 
     x) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 541; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 542: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 541) 
               
               
                   
                 5′-GAACAACUCCUUUUAUGGZ 37 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 542) 
               
               
                   
                 5′-Z 38 CCAUAAAAGGAGUUGUUC-3′, 
               
            
           
         
       
     
     wherein, Z 37  is A, Z 38  is U, the nucleotide sequence I comprises a nucleotide Z 39  at a corresponding site to Z 37 , the nucleotide sequence II comprises a nucleotide Z 40  at a corresponding site to Z 38 , and Z 40  is the first nucleotide from the 5′ terminal of the antisense strand; 
     xi) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 601; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 602: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 601) 
               
               
                   
                 5′-CUUGCUCUGAAGUAGAAAZ 41 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 602) 
               
               
                   
                 5′-Z 42 AUUUCUACUUCAGAGCAAG-3′, 
               
            
           
         
       
     
     wherein, Z 41  is U, Z 42  is A, the nucleotide sequence I comprises a nucleotide Z 43  at a corresponding site to Z 41 , the nucleotide sequence II comprises a nucleotide Z 44  at a corresponding site to Z 42 , and Z 44  is the first nucleotide from the 5′ terminal of the antisense strand; and 
     xii) the nucleotide sequence I has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 661; and the nucleotide sequence II has the same length and no more than three nucleotides differences from the nucleotide sequence shown in SEQ ID NO: 662: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 661) 
               
               
                   
                 5′-CUUCUUUGCCAUCAAAGAZ 45 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 662) 
               
               
                   
                 5′-Z 46 UCUUUGAUGGCAAAGAAG-3′, 
               
            
           
         
       
     
     wherein, Z 45  is U, Z 46  is A, the nucleotide sequence I comprises a nucleotide Z 47  at a corresponding site to Z 45 , the nucleotide sequence II comprises a nucleotide Z 48  at a corresponding site to Z 46 , and Z 48  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the siRNA of the present disclosure and a pharmaceutically acceptable carrier. 
     In some embodiments, the present disclosure provides an siRNA conjugate, wherein the siRNA conjugate comprises the siRNA provided by the present disclosure and a conjugating group conjugatively linked to the siRNA. 
     In some embodiments, the present disclosure provides use of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate according to the present disclosure in the manufacture of a medicament for treating and/or preventing abnormal uric acid metabolism or a disease or a physiological condition caused by abnormal uric acid metabolism. 
     In some embodiments, the present disclosure provides a method for treating and/or preventing abnormal uric acid metabolism or a disease or a physiological condition caused by abnormal uric acid metabolism, wherein the method comprises administering an effective amount of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure to a subject in need. 
     In some embodiments, the present disclosure provides a method for inhibiting expression of an XO gene in a hepatocyte, wherein the method comprises contacting an effective amount of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure to the hepatocyte. 
     In some embodiments, the present disclosure provides a kit, wherein the kit comprises the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure. 
     INCORPORATED BY REFERENCE 
     All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent as each individual publication, patent or patent application is specifically and individually incorporated herein by reference. 
     Advantageous Effects 
     In some embodiments, the siRNA, the pharmaceutical composition and the siRNA conjugate provided by the present disclosure have better stability, higher XO mRNA inhibitory activity and lower off-target effect, and/or can significantly treat or relieve abnormal uric acid metabolism or a disease or a physiological condition caused by abnormal uric acid metabolism, especially hyperuricemia and/or gout symptom. 
     In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits excellent target gene inhibitory activity in cell experiments in vitro. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to target gene expression in hepatocytes of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the siRNA provided by the present disclosure has high inhibitory activity on XO mRNA in an in vitro psiCHECK system, and has certain inhibitory effects on XO target sequences at different siRNA concentrations, and in particular, the inhibitory rate on target sequences at 0.1 nM concentration is at least 61.39%, even as high as 85.43%. In some embodiments, the siRNA provided by the present disclosure exhibits higher inhibitory activity in CAL-27 cells, and the IC 50  for XO mRNA is between 0.037 μM and 0.3277 μM. In some embodiments, the siRNA conjugate provided by the present disclosure shows high inhibitory activity in primary hepatocytes of mice, and the inhibition percentage to XO mRNA is at least 78.95%, even as high as 88.07% under the siRNA concentration of 20 nM. 
     In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure may exhibit higher stability and/or higher activity in vivo. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to target gene expression in hepatocytes of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in vivo. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to XO gene expression in hepatocytes of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in vivo. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to XO gene expression in liver of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in vivo. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to XO gene expression in liver in animal models of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in vivo. In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits an inhibition percentage to XO gene expression in liver in human subjects of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% in vivo. In some embodiments, under the siRNA concentration of 3 mg/kg, the inhibition percentage of the siRNA conjugate provided by the present disclosure to XO mRNA expression in mice is between 70.9% and 76.2%. 
     In some embodiments, the siRNA, the pharmaceutical composition or the siRNA conjugate provided by the present disclosure exhibits no significant off-target effect. An off-target effect may be, for example, inhibition on normal expression of a gene which is not the target gene. It is considered insignificant if the binding/inhibition of off-target gene expression is at a level of lower than 50%, 40%, 30%, 20%, or 10% of the on-target effect. 
     In this way, it is indicated that the siRNA, the pharmaceutical composition and the siRNA conjugate provided by the present disclosure can inhibit the expression of XO gene, can effectively treat and/or prevent abnormal uric acid metabolism or the disease or physiological condition caused by abnormal uric acid metabolism, and have good application prospects. 
     Other features and advantages of the present disclosure will be described in detail in the detailed description section that follows. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIGS. 1A-1F  are dose-response curves fitted according to relative expression levels of XO mRNA in CAL-27 cells in vitro after transfection of different siRNAs. 
         FIG. 2  is a histogram showing the relative expression level of XO mRNA in primary hepatocytes of mice after transfection of different siRNAs. 
         FIG. 3  is a scatter diagram of the relative expression level of XO mRNA in mice after administration of 3 mg/kg of different siRNA conjugates. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The specific embodiments of the present disclosure are described in detail as below. It should be understood that the specific embodiments described herein are only for the purpose of illustration and explanation of the present disclosure and are not intended to limit the present disclosure. 
     In the present disclosure, XO mRNA refers to the mRNA with the sequence shown in Genbank registration number NM_000379.3. Furthermore, unless otherwise stated, the term “target gene” used in the present disclosure refers to a gene capable of transcribing the above XO mRNA, and the term “target mRNA” refers to the above XO mRNA. 
     Definitions 
     In the context of the present disclosure, unless otherwise specified, capital letters C, G, U, and A indicate the base composition of the nucleotides; the lowercase m indicates that the nucleotide adjacent to the left side of the letter m is a methoxy modified nucleotide; the lowercase f indicates that the nucleotide adjacent to the left side of the letter f is a fluoro modified nucleotide; the lowercase letter s indicates that the two nucleotides adjacent to the left and right of the letter s are linked by phosphorothioate; P1 represents that the nucleotide adjacent to the right side of P1 is a 5′-phosphate nucleotide or a 5′-phosphate analogue modified nucleotide, the letter combination VP represents that the nucleotide adjacent to the right side of the letter combination VP is a vinyl phosphate modified nucleotide, the letter combination Ps represents that the nucleotide adjacent to the right side of the letter combination Ps is a phosphorothioate modified nucleotide, and the capital letter P represents that the nucleotide adjacent to the right side of the letter P is a 5′-phosphate nucleotide. 
     In the context of the present disclosure, the “fluoro modified nucleotide” refers to a nucleotide formed by substituting a 2′-hydroxy of a ribose group of the nucleotide with a fluoro, and the “non-fluoro modified nucleotide” refers to a nucleotide formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with a non-fluoro group, or a nucleotide analogue. The “nucleotide analogue” refers to a group that can replace a nucleotide in a nucleic acid, while structurally differs from an adenine ribonucleotide, a guanine ribonucleotide, a cytosine ribonucleotide, a uracil ribonucleotide or a thymidine deoxyribonucleotide, such as an isonucleotide, a bridged nucleic acid (BNA) nucleotide or an acyclic nucleotide. The “methoxy modified nucleotide” refers to a nucleotide formed by substituting the 2′-hydroxy of the ribose group with a methoxy group. 
     In the context of the present disclosure, expressions “complementary” and “reverse complementary” can be interchangeably used, and have a well-known meaning in the art, namely, the bases in one strand are complementarily paired with those in the other strand of a double-stranded nucleic acid molecule. In DNA, a purine base adenine (A) is always paired with a pyrimidine base thymine (T) (or uracil (U) in RNAs); and a purine base guanine (G) is always paired with a pyrimidine base cytosine (C). Each base pair comprises a purine and a pyrimidine. While adenines in one strand are always paired with thymines (or uracils) in another strand, and guanines are always paired with cytosines, these two strands are considered as being complementary each other; and the sequence of a strand may be deduced from the sequence of its complementary strand. Correspondingly, a “mispairing” means that in a double-stranded nucleic acid, the bases at corresponding sites are not presented in a manner of being complementarily paired. 
     In the context of the present disclosure, unless otherwise specified, “basically reverse complementary” means that there are no more than 3 base mispairings between two nucleotide sequences. “Substantially reverse complementary” means that there is no more than 1 base mispairing between two nucleotide sequences. “Completely complementary” means that there is no based mispairing between two nucleotide sequences. 
     In the context of the present disclosure, when a nucleotide sequence has “nucleotide difference” from another nucleotide sequence, the bases of the nucleotides at the same position therebetween are changed. For example, if a nucleotide base in the second sequence is A and the nucleotide base at the same position in the first sequence is U, C, G or T, these two nucleotide sequences are considered as having a nucleotide difference at this position. In some embodiments, if a nucleotide at a position is replaced with an abasic nucleotide or a nucleotide analogue, it is also considered that there is a nucleotide difference at the position. 
     In the context of the present disclosure, particularly in the description of the method for preparing the siRNA, the pharmaceutical composition or the siRNA conjugate of the present disclosure, unless otherwise specified, the nucleoside monomer refers to, according to the kind and sequence of the nucleotides in the siRNA or siRNA conjugate to be prepared, unmodified or modified RNA phosphoramidites used in a solid phase phosphoramidite synthesis (the RNA phosphoramidites are also called as Nucleoside phosphoramidites elsewhere). Solid phase phosphoramidite synthesis is a well-known method used in RNA synthesis to those skilled in the art. Nucleoside monomers used in the present disclosure can all be commercially available. 
     In the context of the present disclosure, unless otherwise stated, “conjugating” refers to two or more chemical moieties each with specific function being linked to each other via a covalent linkage. Correspondingly, a “conjugate” refers to a compound formed by covalent linkage of individual chemical moieties. Further, an “siRNA conjugate” represents a compound formed by covalently linking one or more chemical moieties with specific functions to siRNA. Hereinafter, the siRNA conjugate of the present disclosure is sometimes abbreviated as “conjugate”. The siRNA conjugate should be understood according to the context as the generic term of the siRNA conjugates or the generic term of the siRNA conjugates as shown by Formula (305) and Formula (307), or the siRNA conjugates as shown by Formula (305), Formula (307), and Formula (308). In the context of the present disclosure, a “conjugating molecule” should be understood as a specific compound capable of being conjugated to an siRNA via reactions, thus finally forming the siRNA conjugate of the present disclosure. 
     As used herein, “optional” or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes instances wherein the event or condition may or may not occur. For example, “optionally substituted” “alkyl” encompasses both “alkyl” and “substituted alkyl” as defined below. Those skilled in the art would understand, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically infeasible and/or inherently unstable. 
     As used herein, “alkyl” refers to straight chain and branched chain having the indicated number of carbon atoms, usually 1 to 20 carbon atoms, for example 1 to 10 carbon atoms, such as 1 to 8 or 1 to 6 carbon atoms. For example, C 1 -C 6  alkyl encompasses both straight and branched chain alkyl of 1 to 6 carbon atoms. When naming an alkyl residue having a specific number of carbon atoms, all branched and straight chain forms having that number of carbon atoms are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; and “propyl” includes n-propyl and isopropyl. Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two attachment positions. 
     As used herein, “alkenyl” refers to an unsaturated branched or linear alkyl having at least one carbon-carbon double bond which is obtained by respectively removing one hydrogen molecule from two adjacent carbon atoms of the parent alkyl. The group may be in either cis or trans configuration of the double bond. Typical alkenyl groups include, but not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl; and butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms, and in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkenylene is a subset of alkenyl, referring to the same residues as alkenyl, but having two attachment positions. 
     As used herein, “alkynyl” refers to an unsaturated branched or linear alkyl having at least one carbon-carbon triple bond which is obtained by respectively removing two hydrogen molecules from two adjacent carbon atoms of the parent alkyl. Typical alkynyl groups include, but not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, and prop-2-yn-1-yl; and butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms, and in other embodiments, 2 to 10, 2 to 8, or 2 to 6 carbon atoms. Alkynylene is a subset of alkynyl, referring to the same residues as alkynyl, but having two attachment positions. 
     As used herein, “alkoxy” refers to an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge, such as, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. An alkoxy usually has 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms attached through oxygen bridge. 
     As used herein, “aryl” refers to a group derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e., containing a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. Aryl groups include, but not limited to, phenyl, fluorenyl, naphthyl and the like. Arylene is a subset of aryl, referring to the same residues as aryl, but having two attachment positions. 
     As used herein, “halo substituent” or “ halogen” refers to fluoro, chloro, bromo, and iodo, and the term “halogen” includes fluorine, chlorine, bromine, or iodine. 
     As used herein, “haloalkyl” refers to the alkyl as defined above with the specified number of carbon atoms being substituted with one or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl. 
     “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen or sulfur. Unless stated otherwise in the description, heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl is partially or fully saturated. The heterocyclyl may be linked to the rest of the molecule through any atom of the ring. Examples of such heterocyclyl include, but not limited to, dioxanyl, thienyl[1,3]disulfonyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxapiperazinyl, 2-oxapiperidinyl, 2-oxapyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. 
     “Heteroaryl” refers to a group derived from a 3- to 18-membered aromatic ring radical that comprises 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., containing a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be linked to the rest of the molecule through any atom of the ring. Examples of such heteroaryl include, but not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxazolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d] pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl/thienyl. 
     Various hydroxy protecting groups may be used in the present disclosure. In general, protecting groups render chemical functionalities inert to specific reaction conditions, and may be attached to and removed from such functionalities in a molecule without substantially damaging the remainder of the molecule. Representative hydroxy protecting groups are disclosed in Tetrahedron 1992, 48, 2223-2311 written by Beaucage, et al., and also in Greene and Wuts, Protective Groups in Organic Synthesis, Chapter 2, 2d ed, John Wiley &amp; Sons, New York, 1991, each of which is hereby incorporated by reference in their entirety. In some embodiments, the protecting group is stable under basic conditions but can be removed under acidic conditions. In some embodiments, non-exclusive examples of the hydroxy protecting groups used herein include dimethoxytrityl (DMT), monomethoxytrityl, 9-phenylxanthen-9-yl (Pixyl), or 9-(p-methoxyphenyl)xanthen-9-yl (Mox). In some embodiments, non-exclusive examples of the hydroxy protecting groups used herein include Tr(trityl), MMTr(4-methoxytrityl), DMTr(4,4′-dimethoxytrityl), or TMTr(4,4′,4″-trimethoxytrityl). 
     The term “subject”, as used herein, refers to any animal, e.g., mammal or marsupial. The subject of the present disclosure includes, but not limited to, human, non-human primate (e.g., rhesus or other kinds of macaque), mouse, pig, horse, donkey, cow, sheep, rat or any kind of poultry. 
     As used herein, “treatment” refers to a method for obtaining advantageous or desired result, including but not limited to, therapeutic benefit. “Therapeutic benefit” means eradication or improvement of potential disorder to be treated. Moreover, the therapeutic benefit is achieved by eradicating or ameliorating one or more of physiological symptoms associated with the potential disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the potential disorder. 
     As used herein, “prevention” refers to a method for obtaining advantageous or desired result, including but not limited to, prophylactic benefit. For obtaining the “prophylactic benefit”, the siRNA, the siRNA conjugate or the pharmaceutical composition may be administered to the subject at risk of developing a particular disease, or to the subject reporting one or more physiological symptoms of a disease, even though the diagnosis of this disease may not have been made. 
     In one aspect, the present disclosure provides first to twelfth siRNAs capable of inhibiting expression of an XO gene. The siRNAs will be described in detail hereinafter. 
     The siRNA of the present disclosure comprises nucleotides as basic structural units. It is well-known to those skilled in the art that the nucleotide comprises a phosphate group, a ribose group and a base. Detailed illustrations relating to such groups are omitted herein. 
     The First siRNA 
     According to the present disclosure, the siRNA may be the first siRNA. 
     The first siRNA comprises a sense strand and an antisense strand. Each nucleotide in the first siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 1; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 2: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 1) 
               
               
                   
                 5′-GAGAUGAAGUUCAAGAAUZ 1 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 2) 
               
               
                   
                 5′-Z 2 AUUCUUGAACUUCAUCUC-3′, 
               
            
           
         
       
     
     wherein, Z 1  is A, Z 2  is U, the nucleotide sequence I comprises a nucleotide Z 3  at a corresponding site to Z 1 , the nucleotide sequence II comprises a nucleotide Z 4  at a corresponding site to Z 2 , and Z 4  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In this context, the term “corresponding site” means being at the same site in the nucleotide sequence by counting from the same terminal of the nucleotide sequence. For example, the first nucleotide at the 3′ terminal of the nucleotide sequence I is a nucleotide at the corresponding site to the first nucleotide at the 3′ terminal of SEQ ID NO: 1. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 1, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 2. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 2 comprises a difference at the site of Z 4 , and Z 4  is selected from A, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 4 , and Z 4  is selected from A, C or G. In some embodiments, Z 3  is a nucleotide complementary to Z 4 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. The basically reverse complementary refers to no more than three base mispairings between two nucleotide sequences; the substantially reverse complementary refers to no more than one base mispairing between two nucleotide sequences; and the completely reverse complementary refers to no base mispairing between two nucleotide sequences. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 3, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 4: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 3) 
               
               
                   
                 5′-GAGAUGAAGUUCAAGAAUZ 3 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 4) 
               
               
                   
                 5′-Z 4 AUUCUUGAACUUCAUCUC-3′, 
               
            
           
         
       
     
     wherein, Z 4  is the first nucleotide from 5′ terminal of the antisense strand; Z 4  is selected from A, U, G or C; and Z 3  is a nucleotide complementary to Z 4 ; and in some embodiments, Z 3  is A, and Z 4  is U. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. In this way, a length ratio of the sense strand to the antisense strand of the siRNA provided by the present disclosure may be 19/19, 19/20, 19/21, 19/22, 19/23, 19/24, 19/25, 19/26, 20/20, 20/21, 20/22, 20/23, 20/24, 20/25, 20/26, 21/20, 21/21, 21/22, 21/23, 21/24, 21/25, 21/26, 22/20, 22/21, 22/22, 22/23, 22/24, 22/25, 22/26, 23/20, 23/21, 23/22, 23/23, 23/24, 23/25 or 23/26. In some embodiments, the length ratio of the sense strand to the antisense strand of the siRNA is 19/21, 21/23 or 23/25. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. In some embodiments, the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 1 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is U, and the base of the nucleotide sequence IV is A; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UU, and the base composition of the nucleotide sequence IV is AA; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AUU, and the base composition of the nucleotide sequence IV is AAU; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CAUU, and the base composition of the nucleotide sequence IV is AAUG; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UU, and the base composition of the nucleotide sequence IV is AA; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Second siRNA 
     According to the present disclosure, the siRNA may be the second siRNA. 
     The second siRNA comprises a sense strand and an antisense strand. Each nucleotide in the second siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 61; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 62: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 61) 
               
               
                   
                 5′-CAUAACUGGAAUUUGUAAZ 5 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 62) 
               
               
                   
                 5′-Z 6 UUACAAAUUCCAGUUAUG-3′, 
               
            
           
         
       
     
     wherein, Z 5  is U, Z 6  is A, the nucleotide sequence I comprises a nucleotide Z 7  at a corresponding site to Z 5 , the nucleotide sequence II comprises a nucleotide Z 8  at a corresponding site to Z 6 , and Z 8  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 61, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 62. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 62 comprises a difference at the site of Z 8 , and Z 8  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 8 , and Z 8  is selected from U, C or G. In some embodiments, Z 7  is a nucleotide complementary to Z 8 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 63, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 64: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 63) 
               
               
                   
                 5′-CAUAACUGGAAUUUGUAAZ 7 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 64) 
               
               
                   
                 5′-Z 8 UUACAAAUUCCAGUUAUG-3′, 
               
            
           
         
       
     
     wherein, Z 8  is the first nucleotide from 5′ terminal of the antisense strand; Z 8  is selected from A, U, G or C; and Z 7  is a nucleotide complementary to Z 8 ; and in some embodiments, Z 7  is U, and Z 8  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 61 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UAA, and the base composition of the nucleotide sequence IV is UUA; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GUAA, and the base composition of the nucleotide sequence IV is UUAC; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Third siRNA 
     According to the present disclosure, the siRNA may be the third siRNA. 
     The third siRNA comprises a sense strand and an antisense strand. Each nucleotide in the third siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 121; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 122: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 121) 
               
               
                   
                 5′-CAUUAUCACAAUUGAGGAZ 9 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 122) 
               
               
                   
                 5′-Z 10 UCCUCAAUUGUGAUAAUG-3′, 
               
            
           
         
       
     
     wherein, Z 9  is U, Z 10  is A, the nucleotide sequence I comprises a nucleotide Z 11  at a corresponding site to Z 9 , the nucleotide sequence II comprises a nucleotide Z 12  at a corresponding site to Z 10 , and Z 12  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 121, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 122. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 122 comprises a difference at the site of Z 12 , and Z 12  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 12 , and Z 12  is selected from U, C or G. In some embodiments, Z 11  is a nucleotide complementary to Z 12 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 123, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 124: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 123) 
               
               
                   
                 5′-CAUUAUCACAAUUGAGGAZ 11 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 124) 
               
               
                   
                 5′-Z 12 UCCUCAAUUGUGAUAAUG-3′, 
               
            
           
         
       
     
     wherein, Z 12  is the first nucleotide from 5′ terminal of the antisense strand; Z 12  is selected from A, U, G or C; and Z 11  is a nucleotide complementary to Z 12 ; and in some embodiments, Z 11  is U, and Z 12  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 121 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is C, and the base of the nucleotide sequence IV is G; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GC, and the base composition of the nucleotide sequence IV is GC; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AGC, and the base composition of the nucleotide sequence IV is GCU; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CAGC, and the base composition of the nucleotide sequence IV is GCUG; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GC, and the base composition of the nucleotide sequence IV is GC; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Fourth siRNA 
     According to the present disclosure, the siRNA may be the fourth siRNA. 
     The fourth siRNA comprises a sense strand and an antisense strand. Each nucleotide in the fourth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 181; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 182: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 181) 
               
               
                   
                 5′-GGAUCUCUCUCAGAGUAUZ 13 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 182) 
               
               
                   
                 5′-Z 14 AUACUCUGAGAGAGAUCC-3′, 
               
            
           
         
       
     
     wherein, Z 13  is U, Z 14  is A, the nucleotide sequence I comprises a nucleotide Z 15  at a corresponding site to Z 13 , the nucleotide sequence II comprises a nucleotide Z 16  at a corresponding site to Z 14 , and Z 16  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 181, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 182. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 182 comprises a difference at the site of Z 16 , and Z 16  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 16 , and Z 16  is selected from U, C or G. In some embodiments, Z 15  is a nucleotide complementary to Z 16 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 183, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 184: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 183) 
               
               
                   
                 5′-GGAUCUCUCUCAGAGUAUZ 15 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 184) 
               
               
                   
                 5′-Z 16 AUACUCUGAGAGAGAUCC-3′, 
               
            
           
         
       
     
     wherein, Z 16  is the first nucleotide from 5′ terminal of the antisense strand; Z 16  is selected from A, U, G or C; and Z 15  is a nucleotide complementary to Z 16 ; and in some embodiments, Z 15  is U, and Z 16  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 181 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CA, and the base composition of the nucleotide sequence IV is UG; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CCA, and the base composition of the nucleotide sequence IV is UGG; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CCCA, and the base composition of the nucleotide sequence IV is UGGG; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CA, and the base composition of the nucleotide sequence IV is UG; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Fifth siRNA 
     According to the present disclosure, the siRNA may be the fifth siRNA. 
     The fifth siRNA comprises a sense strand and an antisense strand. Each nucleotide in the fifth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 241; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 242: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 241) 
               
               
                   
                 5′-ACAUGGACAACUGCUAUAZ 17 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 242) 
               
               
                   
                 5′-Z 18 UAUAGCAGUUGUCCAUGU-3′, 
               
            
           
         
       
     
     wherein, Z 17  is A, Z 18  is U, the nucleotide sequence I comprises a nucleotide Z 10  at a corresponding site to Z 17 , the nucleotide sequence II comprises a nucleotide Z 20  at a corresponding site to Z 18 , and Z 20  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 241, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 242. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 242 comprises a difference at the site of Z 20 , and Z 20  is selected from A, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 20 , and Z 20  is selected from A, C or G. In some embodiments, Z 19  is a nucleotide complementary to Z 20 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 243, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 244: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 243) 
               
               
                   
                 5′-ACAUGGACAACUGCUAUAZ 19 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 244) 
               
               
                   
                 5′-Z 20 UAUAGCAGUUGUCCAUGU-3′, 
               
            
           
         
       
     
     wherein, Z 20  is the first nucleotide from 5′ terminal of the antisense strand; Z 20  is selected from A, U, G or C; and Z 19  is a nucleotide complementary to Z 20 ; and in some embodiments, Z 19  is A, and Z 20  is U. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 241 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is C, and the base of the nucleotide sequence IV is G; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CC, and the base composition of the nucleotide sequence IV is GG; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UCC, and the base composition of the nucleotide sequence IV is GGA; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UUCC, and the base composition of the nucleotide sequence IV is GGAA; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CC, and the base composition of the nucleotide sequence IV is GG; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Sixth siRNA 
     According to the present disclosure, the siRNA may be the sixth siRNA. 
     The sixth siRNA comprises a sense strand and an antisense strand. Each nucleotide in the sixth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 301; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 302: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 301) 
               
               
                   
                 5′-UAGCAAGCUCUCAGUAUCZ 21 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 302) 
               
               
                   
                 5′-Z 22 GAUACUGAGAGCUUGCUA-3′, 
               
            
           
         
       
     
     wherein, Z 21  is A, Z 22  is U, the nucleotide sequence I comprises a nucleotide Z 23  at a corresponding site to Z 21 , the nucleotide sequence II comprises a nucleotide Z 24  at a corresponding site to Z 22 , and Z 24  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 301, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 302. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 302 comprises a difference at the site of Z 24 , and Z 24  is selected from A, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 24 , and Z 24  is selected from A, C or G. In some embodiments, Z 23  is a nucleotide complementary to Z 24 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 303, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 304: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 303) 
               
               
                   
                 5′-UAGCAAGCUCUCAGUAUCZ 23 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 304) 
               
               
                   
                 5′-Z 24 GAUACUGAGAGCUUGCUA-3′, 
               
            
           
         
       
     
     wherein, Z 24  is the first nucleotide from 5′ terminal of the antisense strand; Z 24  is selected from A, U, G or C; and Z 23  is a nucleotide complementary to Z 24 ; and in some embodiments, Z 23  is A, and Z 24  is U. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 301 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is C, and the base of the nucleotide sequence IV is G; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CC, and the base composition of the nucleotide sequence IV is GG; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GCC, and the base composition of the nucleotide sequence IV is GGC; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UGCC, and the base composition of the nucleotide sequence IV is GGCA; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CC, and the base composition of the nucleotide sequence IV is GG; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Seventh siRNA 
     According to the present disclosure, the siRNA may be the seventh siRNA. 
     The seventh siRNA comprises a sense strand an antisense strand. Each nucleotide in the seventh siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 361; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 362: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 361) 
               
               
                   
                 5′-AUAAGGUUACUUGUGUUGZ 25 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 362) 
               
               
                   
                 5′-Z 26 CAACACAAGUAACCUUAU-3′, 
               
            
           
         
       
     
     wherein, Z 25  is G, Z 6  is C, the nucleotide sequence I comprises a nucleotide Z 27  at a corresponding site to Z 25 , the nucleotide sequence II comprises a nucleotide Z 28  at a corresponding site to Z 26 , and Z 28  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 361, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 362. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 362 comprises a difference at the site of Z 28 , and Z 28  is selected from A, U or G. In some embodiments, the nucleotide difference is a difference at the site of Z 28 , and Z 28  is selected from A, U or G. In some embodiments, Z 27  is a nucleotide complementary to Z 28 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 363, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 364: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 363) 
               
               
                   
                 5′-AUAAGGUUACUUGUGUUGZ 27 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 364) 
               
               
                   
                 5′-Z 28 CAACACAAGUAACCUUAU-3′, 
               
            
           
         
       
     
     wherein, Z 28  is the first nucleotide from 5′ terminal of the antisense strand; Z 28  is selected from A, U, G or C; and Z 27  is a nucleotide complementary to Z 28 ; and in some embodiments, Z 27  is and Z 28  is C. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. In some embodiments, the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 362 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is and the base of the nucleotide sequence IV is C; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AGG, and the base composition of the nucleotide sequence IV is CCU; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AAGG, and the base composition of the nucleotide sequence IV is CCUU; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Eighth siRNA 
     According to the present disclosure, the siRNA may be the eighth siRNA. 
     The eighth siRNA comprises a sense strand an antisense strand. Each nucleotide in the eighth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 421; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 422: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 421) 
               
               
                   
                 5′-GAAAAUCACCUAUGAAGAZ 29 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 422) 
               
               
                   
                 5′-Z 30 UCUUCAUAGGUGAUUUUC-3′, 
               
            
           
         
       
     
     wherein, Z 29  is A, Z 30  is U, the nucleotide sequence I comprises a nucleotide Z 31  at a corresponding site to Z 29 , the nucleotide sequence II comprises a nucleotide Z 32  at a corresponding site to Z 30 , and Z 32  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 421, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 422. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 422 comprises a difference at the site of Z 32 , and Z 32  is selected from A, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 32 , and Z 32  is selected from A, C or G. In some embodiments, Z 31  is a nucleotide complementary to Z 32 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 423, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 424: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 423) 
               
               
                   
                 5′-GAAAAUCACCUAUGAAGAZ 31 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 424) 
               
               
                   
                 5′-Z 32 UCUUCAUAGGUGAUUUUC-3′, 
               
            
           
         
       
     
     wherein, Z 32  is the first nucleotide from 5′ terminal of the antisense strand; Z 32  is selected from A, U, G or C; and Z 31  is a nucleotide complementary to Z 32 ; and in some embodiments, Z 31  is A, and Z 32  is U. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. In some embodiments, the nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 421 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is U, and the base of the nucleotide sequence IV is A; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GU, and the base composition of the nucleotide sequence IV is AC; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GGU, and the base composition of the nucleotide sequence IV is ACC; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GGGU, and the base composition of the nucleotide sequence IV is ACCC; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GU, and the base composition of the nucleotide sequence IV is AC; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Ninth siRNA 
     According to the present disclosure, the siRNA may be the ninth siRNA. 
     The ninth siRNA comprises a sense strand an antisense strand. Each nucleotide in the ninth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 481; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 482: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 481) 
               
               
                   
                 5′-GAUGCUAUAAAGAACAACZ 33 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 482) 
               
               
                   
                 5′-Z 34 GUUGUUCUUUAUAGCAUC-3′, 
               
            
           
         
       
     
     wherein, Z 33  is U, Z 34  is A, the nucleotide sequence I comprises a nucleotide Z 35  at a corresponding site to Z 33 , the nucleotide sequence II comprises a nucleotide Z 36  at a corresponding site to Z 34 , and Z 36  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 481, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 482. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 482 comprises a difference at the site of Z 36 , and Z 36  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 36 , and Z 36  is selected from U, C or G. In some embodiments, Z 35  is a nucleotide complementary to Z 36 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 483, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 484: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 483) 
               
               
                   
                 5′-GAUGCUAUAAAGAACAACZ 35 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 484) 
               
               
                   
                 5′-Z 36 GUUGUUCUUUAUAGCAUC-3′, 
               
            
           
         
       
     
     wherein, Z 36  is the first nucleotide from 5′ terminal of the antisense strand; Z 36  is selected from A, U, G or C; and Z 35  is a nucleotide complementary to Z 36 ; and in some embodiments, Z 35  is U, and Z 36  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 4821 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is G, and the base of the nucleotide sequence IV is C; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AG, and the base composition of the nucleotide sequence IV is CU; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GAG, and the base composition of the nucleotide sequence IV is CUC; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UGAG, and the base composition of the nucleotide sequence IV is CUCA; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AG, and the base composition of the nucleotide sequence IV is CU; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Tenth siRNA 
     According to the present disclosure, the siRNA may be the tenth siRNA. 
     The tenth siRNA comprises a sense strand an antisense strand. Each nucleotide in the tenth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 541; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 542: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 541) 
               
               
                   
                 5′-GAACAACUCCUUUUAUGGZ 37 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 542) 
               
               
                   
                 5′-Z 38 CCAUAAAAGGAGUUGUUC-3′, 
               
            
           
         
       
     
     wherein, Z 37  is A, Z 38  is U, the nucleotide sequence I comprises a nucleotide Z 39  at a corresponding site to Z 37 , the nucleotide sequence II comprises a nucleotide Z 40  at a corresponding site to Z 38 , and Z 40  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 541, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 542. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 542 comprises a difference at the site of Z 40 , and Z 40  is selected from A, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 40 , and Z 40  is selected from A, C or G. In some embodiments, Z 39  is a nucleotide complementary to Z 40 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 543, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 544: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 543) 
               
               
                   
                 5′-GAACAACUCCUUUUAUGGZ 39 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 544) 
               
               
                   
                 5′-Z 40 CCAUAAAAGGAGUUGUUC-3′, 
               
            
           
         
       
     
     wherein, Z 40  is the first nucleotide from 5′ terminal of the antisense strand; Z 40  is selected from A, U, G or C; and Z 39  is a nucleotide complementary to Z 40 ; and in some embodiments, Z 39  is A, and Z 40  is U. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 541 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is A, and the base of the nucleotide sequence IV is U; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AAA, and the base composition of the nucleotide sequence IV is UUU; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UAAA, and the base composition of the nucleotide sequence IV is UUUA; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AA, and the base composition of the nucleotide sequence IV is UU; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Eleventh siRNA 
     According to the present disclosure, the siRNA may be the eleventh siRNA. 
     The eleventh siRNA comprises a sense strand an antisense strand. Each nucleotide in the eleventh siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 601; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 602: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 601) 
               
               
                   
                 5′-CUUGCUCUGAAGUAGAAAZ 41 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 602) 
               
               
                   
                 5′-Z 42 AUUUCUACUUCAGAGCAAG-3′, 
               
            
           
         
       
     
     wherein, Z 41  is U, Z 42  is A, the nucleotide sequence I comprises a nucleotide Z 43  at a corresponding site to Z 41 , the nucleotide sequence II comprises a nucleotide Z 44  at a corresponding site to Z 42 , and Z 44  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the sense strand exclusively comprises the nucleotide sequence I, and the antisense strand exclusively comprises the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 601, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 602. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 602 comprises a difference at the site of Z 44 , and Z 44  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 44 , and Z 44  is selected from U, C or G. In some embodiments, Z 43  is a nucleotide complementary to Z 44 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 603, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 604: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 603) 
               
               
                   
                 5′-CUUGCUCUGAAGUAGAAAZ 43 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 604) 
               
               
                   
                 5′-Z 44 UUUCUACUUCAGAGCAAG-3′, 
               
            
           
         
       
     
     wherein, Z 44  is the first nucleotide from 5′ terminal of the antisense strand; Z 44  is selected from A, U, G or C; and Z 43  is a nucleotide complementary to Z 44 ; and in some embodiments, Z 43  is U, and Z 44  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 601 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is and the base of the nucleotide sequence IV is C; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UGG and the base composition of the nucleotide sequence IV is CCA; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GUGG, and the base composition of the nucleotide sequence IV is CCAC; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is GG, and the base composition of the nucleotide sequence IV is CC; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The Twelveth siRNA 
     According to the present disclosure, the siRNA may be the twelveth siRNA. 
     The twelveth siRNA comprises a sense strand an antisense strand. Each nucleotide in the twelveth siRNA is independently a modified or unmodified nucleotide, wherein the sense strand comprises a segment of nucleotide sequence I, the antisense strand comprises a segment of nucleotide sequence II, and the nucleotide sequence I and the nucleotide sequence II are at least partly reverse complementary to form a double-stranded region, wherein the nucleotide sequence I has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 661; and the nucleotide sequence II has the same length and no more than three nucleotide differences from the nucleotide sequence shown in SEQ ID NO: 662: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 661) 
               
               
                   
                 5′-CUUCUUUGCCAUCAAAGAZ 45 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 662) 
               
               
                   
                 5′-Z 46 UCUUUGAUGGCAAAGAAG-3′, 
               
            
           
         
       
     
     wherein, Z 45  is U, Z 46  is A, the nucleotide sequence I comprises a nucleotide Z 47  at a corresponding site to Z 45 , the nucleotide sequence II comprises a nucleotide Z 48  at a corresponding site to Z 46 , and Z 48  is the first nucleotide from the 5′ terminal of the antisense strand. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 661, and/or the nucleotide sequence II has no more than one nucleotide difference from the nucleotide sequence shown in SEQ ID NO: 662. 
     In some embodiments, the nucleotide difference between the nucleotide sequence II and the nucleotide sequence shown in SEQ ID NO: 662 comprises a difference at the site of Z 48 , and Z 48  is selected from U, C or G. In some embodiments, the nucleotide difference is a difference at the site of Z 48 , and Z 48  is selected from U, C or G. In some embodiments, Z 47  is a nucleotide complementary to Z 48 . The siRNAs having the above nucleotide difference has higher ability to inhibit the target mRNA, and these siRNAs comprising the nucleotide differences are also within the scope of the present disclosure. 
     In some embodiments, the nucleotide sequence I is basically reverse complementary, substantially reverse complementary, or completely reverse complementary to the nucleotide sequence II. 
     In some embodiments, the nucleotide sequence I is the nucleotide sequence shown in SEQ ID NO: 663, and the nucleotide sequence II is the nucleotide sequence shown in SEQ ID NO: 664: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 663) 
               
               
                   
                 5′-CUUCUUUGCCAUCAAAGAZ 47 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 664) 
               
               
                   
                 5′-Z 48 UCUUUGAUGGCAAAGAAG-3′, 
               
            
           
         
       
     
     wherein, Z 48  is the first nucleotide from 5′ terminal of the antisense strand; Z 48  is selected from A, U, G or C; and Z 47  is a nucleotide complementary to Z 48;  and in some embodiments, Z 47  is U, and Z 48  is A. 
     Moreover, lengths of the sense strand and the antisense strand are the same or different, the length of the sense strand is 19-23 nucleotides, and the length of the antisense strand is 19-26 nucleotides. 
     In some embodiments, the sense strand further comprises a nucleotide sequence III, the antisense strand further comprises a nucleotide sequence IV, and the nucleotide sequence III and the nucleotide sequence IV each independently have a length of 1-4 nucleotides; the nucleotide sequence III has the same length and is substantially reverse complementary or completely reverse complementary to the nucleotide sequence IV; the nucleotide sequence III is linked to the 5′ terminal of the nucleotide sequence I, and the nucleotide sequence IV is linked to the 3′ terminal of the nucleotide sequence II. The nucleotide sequence IV is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, and the nucleotide sequence II refers to the nucleotide sequence adjacent to the 5′ terminal of the nucleotide sequence represented by SEQ ID NO: 661 in the target mRNA and having the same length as the nucleotide sequence IV. 
     In some embodiments, in the direction from 5′ to 3′, the nucleotide sequence III and the nucleotide sequence IV both have a length of one nucleotide. The base of the nucleotide sequence III is U, and the base of the nucleotide sequence IV is A; in this case, the length ratio of the sense strand to the antisense strand is 20/20; or, the nucleotide sequences III and IV both have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AU, and the base composition of the nucleotide sequence IV is AU; in this case, the length ratio of the sense strand to the antisense strand is 21/21; or, the nucleotide sequences III and IV both have a length of three nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is UAU, and the base composition of the nucleotide sequence IV is AUA; in this case, the length ratio of the sense strand to the antisense strand is 22/22; or, the nucleotide sequences III and IV both have a length of four nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is CUAU, and the base composition of the nucleotide sequence IV is AUAG; in this case, the length ratio of the sense strand to the antisense strand is 23/23. In some embodiments, the nucleotide sequence III and the nucleotide sequence IV have a length of two nucleotides, and in the direction from the 5′ terminal to the 3′ terminal, the base composition of the nucleotide sequence III is AU, and the base composition of the nucleotide sequence IV is AU; in this case, the length ratio of the sense strand to the antisense strand is 21/21. 
     In some embodiments, the nucleotide sequence III is completely reverse complementary to the nucleotide sequence IV. Thus, if the base of the nucleotide sequence III is provided, the base of the nucleotide sequence IV is also determined. 
     The following description of the nucleotide sequence V, the nucleic acid sequence, the nucleotide modification in the siRNA and the modified sequence is applicable to any one of the first siRNA to the twelveth siRNA. That is, unless otherwise specified, the following description of the siRNA should be regarded as describing the first siRNA, the second siRNA, the third siRNA, the fourth siRNA, the fifth siRNA, the sixth siRNA, the seventh siRNA, the eighth siRNA, the ninth siRNA, the tenth siRNA, the eleventh siRNA, and the twelveth siRNA one by one. For example, if no specific siRNA is specified, “the siRNA further comprises a nucleotide sequence V” means “the first siRNA, the second siRNA, the third siRNA, the fourth siRNA, the fifth siRNA, the sixth siRNA, the seventh siRNA, the eighth siRNA, the ninth siRNA, the tenth siRNA, the eleventh siRNA, or the twelveth siRNA further comprises a nucleotide sequence V”. 
     In some embodiments, the sense strand and the antisense strand have different lengths. The nucleotide sequence II further comprises a nucleotide sequence V, which has a length of 1-3 nucleotides and is linked to 3′ terminal of the antisense strand, thereby constituting a 3′ overhang of the antisense strand. As such, the length ratio of the sense strand to the antisense strand in the siRNA of the present disclosure may be 19/20, 19/21, 19/22, 20/21, 20/22, 20/23, 21/22, 21/23, 21/24, 22/23, 22/24, 22/25, 23/24, 23/25, or 23/26. In some embodiments, the nucleotide sequence V has a length of 2 nucleotides. As such, the length ratio of the sense strand to the antisense strand in the siRNA of the present disclosure may be 19/21, 21/23 or 23/25. 
     Each nucleotide in the nucleotide sequence V may be any nucleotide. In order to facilitate synthesis and save synthesis cost, the nucleotide sequence V is 2 continuous thymidine deoxyribonucleotides (dTdT) or 2 continuous uracil ribonucleotides (UU); or, in order to improve the affinity of the antisense strand of the siRNA to the target mRNA, the nucleotide sequence V is complementary to the nucleotide(s0029 at the corresponding site of the target mRNA. Therefore, in some embodiments, the length ratio of the sense strand to the antisense strand of the siRNA of the present disclosure is 19/21 or 21/23. In this case, the siRNA of the present disclosure has better silencing activity against target mRNA. 
     The nucleotide at the corresponding site of the target mRNA refers to one segment of the nucleotide or nucleotide sequence adjacent to the nucleotide sequence I of the target mRNA at the 5′ terminal. This segment of nucleotide sequence of the target mRNA is substantially reverse complementary or completely reverse complementary to the nucleotide sequence II, or, is a segment of nucleotide sequence which is substantially reverse complementary or completely reverse complementary to the nucleotide sequence formed by the nucleotide sequence II and the nucleotide sequence IV. 
     In some embodiments, for the first siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 5, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 6; 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 5) 
               
               
                   
                 5′-GAGAUGAAGUUCAAGAAUZ 3 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 6) 
               
               
                   
                 5′-Z 4 AUUCUUGAACUUCAUCUCAA-3′; 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 7, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 8; 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 7) 
               
               
                   
                 5′-UUGAGAUGAAGUUCAAGAAUZ 3 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 8) 
               
               
                   
                 5′-Z 4 AUUCUUGAACUUCAUCUCAAUG-3′; 
               
            
           
         
       
     
     wherein, Z 4  is the first nucleotide from 5′ terminal of the antisense strand; Z 4  is selected from A, U, G or C; and Z 3  is a nucleotide complementary to Z 4 . 
     In some embodiments, for the second siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 65, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 66: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 65) 
               
               
                   
                 5′-CAUAACUGGAAUUUGUAAZ 7 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 66) 
               
               
                   
                 5′-Z 8 UUACAAAUUCCAGUUAUGUU-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 67, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 68: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 67) 
               
               
                   
                 5′-AACAUAACUGGAAUUUGUAAZ 7 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 68) 
               
               
                   
                 5′-Z 8 UUACAAAUUCCAGUUAUGUUAC-3′, 
               
            
           
         
       
     
     wherein, Z 8  is the first nucleotide from 5′ terminal of the antisense strand; Z 8  is selected from A, U, G or C; and Z 7  is a nucleotide complementary to Z 8 . 
     In some embodiments, for the third siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 125, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 126: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 125) 
               
               
                   
                 5′-CAUUAUCACAAUUGAGGAZ 11 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 126) 
               
               
                   
                 5′-Z 12 UCCUCAAUUGUGAUAAUGGC-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 127, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 128: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 127) 
               
               
                   
                 5′-GCCAUUAUCACAAUUGAGGAZ 11 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 128) 
               
               
                   
                 5′-Z 12 UCCUCAAUUGUGAUAAUGGCUG-3′, 
               
            
           
         
       
     
     wherein, Z 12  is the first nucleotide from 5′ terminal of the antisense strand; Z 12  is selected from A, U, G or C; and Z 11  is a nucleotide complementary to Z 12 . 
     In some embodiments, for the fourth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 185, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 186: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 185) 
               
               
                   
                 5′-GGAUCUCUCUCAGAGUAUZ15-3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 186) 
               
               
                   
                 5′-Z 16 AUACUCUGAGAGAGAUCCUG-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 187, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 188: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 187) 
               
               
                   
                 5′-CAGGAUCUCUCUCAGAGUAUZ 15 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 188) 
               
               
                   
                 5′-Z 16 AUACUCUGAGAGAGAUCCUGGG-3′, 
               
            
           
         
       
     
     wherein, Z 16  is the first nucleotide from 5′ terminal of the antisense strand; Z 16  is selected from A, U, G or C; and Z 15  is a nucleotide complementary to Z 16 . 
     In some embodiments, for the fifth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 245, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 246: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 245) 
               
               
                   
                 5′-ACAUGGACAACUGCUAUAZ 19 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 246) 
               
               
                   
                 5′-Z 20 UAUAGCAGUUGUCCAUGUGG-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 247, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 248: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 247) 
               
               
                   
                 5′-CCACAUGGACAACUGCUAUAZ 19 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 248) 
               
               
                   
                 5′-Z20UAUAGCAGUUGUCCAUGUGGAA-3′, 
               
            
           
         
       
     
     wherein, Z 20  is the first nucleotide from 5′ terminal of the antisense strand; Z 20  is selected from A, U, G or C; and Z 19  is a nucleotide complementary to Z 20 . 
     In some embodiments, for the sixth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 305, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 306: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 305) 
               
               
                   
                 5′-UAGCAAGCUCUCAGUAUCZ 23 -3′; 
               
               
                   
               
               
                   
                 (SEQ ID NO: 306) 
               
               
                   
                 5′-Z 24 GAUACUGAGAGCUUGCUAGG-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 307, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 308: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 307) 
               
               
                   
                 5′-CCUAGCAAGCUCUCAGUAUCZ 23 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 308) 
               
               
                   
                 5′-Z 24 GAUACUGAGAGCUUGCUAGGCA-3′, 
               
            
           
         
       
     
     wherein, Z 24  is the first nucleotide from 5′ terminal of the antisense strand; Z 24  is selected from A, U, G or C; and Z 23  is a nucleotide complementary to Z 24 . 
     In some embodiments, for the seventh siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 365, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 366: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 365) 
               
               
                   
                 5′-AUAAGGUUACUUGUGUUGZ 27 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 366) 
               
               
                   
                 5′-Z 28 CAACACAAGUAACCUUAUCC-3′; 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 367, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 368; 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 367) 
               
               
                   
                 5′-GGAUAAGGUUACUUGUGUUGZ 27 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 368) 
               
               
                   
                 5′-Z 28 CAACACAAGUAACCUUAUCCUU-3′, 
               
            
           
         
       
     
     wherein, Z 28  is the first nucleotide from 5′ terminal of the antisense strand; Z 28  is selected from A, U, G or C; and Z 27  is a nucleotide complementary to Z 28 . 
     In some embodiments, for the eighth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 425, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 426: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 425) 
               
               
                   
                 5′-GAAAAUCACCUAUGAAGAZ 31 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 426) 
               
               
                   
                 5′-Z 32 UCUUCAUAGGUGAUUUUCAC-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 427, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 428: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 427) 
               
               
                   
                 5′-GUGAAAAUCACCUAUGAAGAZ 31 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 428) 
               
               
                   
                 5′-Z 32 UCUUCAUAGGUGAUUUUCACCC-3′, 
               
            
           
         
       
     
     wherein, Z 32  is the first nucleotide from 5′ terminal of the antisense strand; Z 32  is selected from A, U, G or C; and Z 31  is a nucleotide complementary to Z 32 . 
     In some embodiments, for the ninth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 485, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 486: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 485) 
               
               
                   
                 5′-GAUGCUAUAAAGAACAACZ 35 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 486) 
               
               
                   
                 5′-Z 36 GUUGUUCUUUAUAGCAUCCU-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 487, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 488: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 487) 
               
               
                   
                 5′-AGGAUGCUAUAAAGAACAACZ 35 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 488) 
               
               
                   
                 5′-Z 36 GUUGUUCUUUAUAGCAUCCUCA-3′, 
               
            
           
         
       
     
     wherein, Z 36  is the first nucleotide from 5′ terminal of the antisense strand; Z 36  is selected from A, U, G or C; and Z 35  is a nucleotide complementary to Z 36 . 
     In some embodiments, for the tenth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 545, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 546: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 545) 
               
               
                   
                 5′-GAACAACUCCUUUUAUGGZ 39 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 546) 
               
               
                   
                 5′-Z 40 CCAUAAAAGGAGUUGUUCUU-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 547, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 548: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 547) 
               
               
                   
                 5′-AAGAACAACUCCUUUUAUGGZ 39 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 548) 
               
               
                   
                 5′-Z 40 CCAUAAAAGGAGUUGUUCUUUA-3′, 
               
            
           
         
       
     
     wherein, Z 40  is the first nucleotide from 5′ terminal of the antisense strand; Z 40  is selected from A, U, G or C; and Z 39  is a nucleotide complementary to Z 40 . 
     In some embodiments, for the eleventh siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 605, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 606: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 605) 
               
               
                   
                 5′-CUUGCUCUGAAGUAGAAAZ 43 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 606) 
               
               
                   
                 5′-Z 44 UUUCUACUUCAGAGCAAGCC-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 607, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 608: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 607) 
               
               
                   
                 5′-GGCUUGCUCUGAAGUAGAAAZ 43 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 608) 
               
               
                   
                 5′-Z 44 UUUCUACUUCAGAGCAAGCCAC-3′, 
               
            
           
         
       
     
     wherein, Z 44  is the first nucleotide from 5′ terminal of the antisense strand; Z 44  is selected from A, U, G or C; and Z 43  is a nucleotide complementary to Z 44 . 
     In some embodiments, for the twelveth siRNA, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 665, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 666: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 665) 
               
               
                   
                 5′-CUUCUUUGCCAUCAAAGAZ 47 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 666) 
               
               
                   
                 5′-Z 48 UCUUUGAUGGCAAAGAAGAU-3′, 
               
            
           
         
       
     
     or, the sense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 667, and the antisense strand of the siRNA comprises the nucleotide sequence shown in SEQ ID NO: 668: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 667) 
               
               
                   
                 5′-AUCUUCUUUGCCAUCAAAGAZ 47 -3′; 
               
               
                   
                   
               
               
                   
                 (SEQ ID NO: 668) 
               
               
                   
                 5′-Z 48 UCUUUGAUGGCAAAGAAGAUAG-3′, 
               
            
           
         
       
     
     wherein, Z 48  is the first nucleotide from 5′ terminal of the antisense strand; Z 48  is selected from A, U, G or C; and Z 47  is a nucleotide complementary to Z 48 . 
     In some embodiments, the siRNA of the present disclosure is any one of siXOa1, siXOa2, siXOb1, siXOb2, siXOc1, siXOc2, siXOd1, siXOd2, siXOe1, siXOe2, siXOf1, siXOf2, siXOg1, siXOg2, siXOh1, siXOh2, siXOi1, siXOi2, siXOj1, siXOj2, siXOk1, siXOk2, siXOl1 and siXOl2 listed in Tables 1a-1l. 
     As described above, the nucleotides in the siRNA of the present disclosure are each independently modified or unmodified nucleotides. In some embodiments, each nucleotide in the siRNA of the present disclosure is an unmodified nucleotide. In some embodiments, some or all nucleotides in the siRNA of the present disclosure are modified nucleotides. Such modifications on the nucleotides would not cause significant decrease or loss of the function of the siRNA conjugate of the present disclosure to inhibit the expression of XO genes. 
     In some embodiments, the siRNA of the present disclosure comprises at least one modified nucleotide. In the context of the present disclosure, the term “modified nucleotide” employed herein refers to a nucleotide formed by substituting a 2′-hydroxy of a ribose group of a nucleotide with other groups, a nucleotide analogue, or a nucleotide with modified base. Such modified nucleotides would not cause significant decrease or loss of the function of the siRNA to inhibit the expression of genes. For example, the modified nucleotides disclosed in Chemically Modified siRNA: tools and applications. Drug Discov Today, 2008.13(19-20): p. 842-55 written by J. K. Watts, G F. Deleavey and M. J. Damha may be selected. 
     In some embodiments, at least one nucleotide in the sense strand or the antisense strand of the siRNA provided by the present disclosure is a modified nucleotide, and/or at least one phosphate is a phosphate group with modified group. In other words, at least a portion of the phosphate group and/or ribose group in phosphate-ribose backbone of at least one single strand in the sense strand and the antisense strand are phosphate group with modified group and/or ribose group with modified group. 
     In some embodiments, all nucleotides in the sense strand and/or the antisense strand are modified nucleotides. In some embodiments, each nucleotide in the sense strand and the antisense strand of the siRNA provided by the present disclosure is independently a fluoro modified nucleotide or a non-fluoro modified nucleotide. 
     The inventors of the present disclosure have surprisingly found that the siRNA of the present disclosure has achieved a high degree of balance between the stability in serum and the gene silencing efficiency in animal experiments. 
     In some embodiments, the fluoro modified nucleotides are located in the nucleotide sequence I and the nucleotide sequence II; and in the direction from 5′ terminal to 3′ terminal, at least the nucleotides at positions 7, 8 and 9 of the nucleotide sequence I are fluoro modified nucleotides; and in the direction from 5′ terminal to 3′ terminal, at least the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence ii are fluoro modified nucleotides. 
     In some embodiments, the fluoro modified nucleotides are located in the nucleotide sequence I and the nucleotide sequence II; no more than 5 fluoro modified nucleotides are present in the nucleotide sequence I, and in the direction from 5′ terminal to 3′ terminal, at least the nucleotides at positions 7, 8 and 9 in the nucleotide sequence I are fluoro modified nucleotides; no more than 7 fluoro modified nucleotides are present in the nucleotide sequence II, and at least the nucleotides at positions 2, 6, 14 and 16 in the nucleotide sequence II are fluoro modified nucleotides. 
     In some embodiments, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 or 5, 7, 8 and 9 of the nucleotide sequence I in the sense strand are fluoro modified nucleotides, and the nucleotides at the rest of positions in the sense strand are non-fluoro modified nucleotides; and in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 14 and 16 or 2, 6, 8, 9, 14 and 16 of the nucleotide sequence II in the antisense strand are fluoro modified nucleotides, and the nucleotides at the rest of positions in the antisense strand are non-fluoro modified nucleotides. 
     In the context of the present disclosure, a “fluoro modified nucleotide” refers to a nucleotide which is formed by substituting a 2′-hydroxy of a ribose group of a nucleotide with fluoro, which has a structure as shown by Formula (7). A “non-fluoro modified nucleotide”, refers to a nucleotide which is formed by substituting a 2′-hydroxy of a ribose group of a nucleotide with a non-fluoro group, or a nucleotide analogue. In some embodiments, each non-fluoro modified nucleotide is independently selected from a nucleotide formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with the non-fluoro group, or the nucleotide analogue. 
     These nucleotides formed by substituting the 2′-hydroxy of the ribose group with the non fluoro group are well-known to those skilled in the art, and these nucleotides may be selected from one of a 2′ alkoxy modified nucleotide, a 2′-substituted alkoxy modified nucleotide, a 2′-alkyl modified nucleotide, a 2′-substituted alkyl modified nucleotide, a 2′-amino modified nucleotide, a 2′ substituted amino modified nucleotide and a 2′-deoxy nucleotide. 
     In some embodiments, the 2′-alkoxy modified nucleotide is a methoxy modified nucleotide (2′-OMe), as shown by Formula (8). In some embodiments, the 2′-substituted alkoxy modified nucleotide is, for example, a 2′-O-methoxyethoxy modified nucleotide (2′ MOE) as shown by Formula (9). In some embodiments, the 2′-amino modified nucleotide (2′-NH 2 ) is as shown by Formula (10). In some embodiments, the 2′-deoxy nucleotide (DNA) is as shown by Formula (11): 
     
       
         
         
             
             
         
       
     
     The nucleotide analogue refers to a group that can replace a nucleotide in a nucleic acid, while structurally differs from an adenine ribonucleotide, a guanine ribonucleotide, a cytosine ribonucleotide, a uracil ribonucleotide or a thymidine deoxyribonucleotide. In some embodiments, the nucleotide analogue may be an isonucleotide, a bridged nucleic acid (referred to as BNA) or an acyclic nucleotide. 
     The BNA is a nucleotide that is constrained or is not accessible. The BNA may contain a 5-membered ring, 6-membered ring or 7-membered ring bridged structure with a “fixed” C3′-endo sugar puckering. The bridge is typically incorporated at the 2′- and 4′-position of the ribose to afford a 2′,4′-BNA nucleotide. In some embodiments, the BNA may be an LNA, an ENA and a cET BNA, wherein the LNA is as shown by Formula (12), the ENA is as shown by Formula (13) and the cET BNA is as shown by Formula (14): 
     
       
         
         
             
             
         
       
     
     An acyclic nucleotide is a nucleotide in which a ribose ring is opened. In some embodiments, the acyclic nucleotide may be an unlocked nucleic acid (UNA) or a glycerol nucleic acid (GNA), wherein the UNA is as shown by Formula (15), and the GNA is as shown by Formula (16): 
     
       
         
         
             
             
         
       
     
     In the Formula (15) and the Formula (16), R is selected from H, OH or alkoxy (O-alkyl). 
     An isonucleotide is a compound which is formed by that a nucleotide in which a position of a base on a ribose ring alters. In some embodiments, the isonucleotide may be a compound in which the base is transposed from position-1′ to position-2′ or position-3′ on the ribose ring, as shown by Formula (17) or (18). 
     
       
         
         
             
             
         
       
     
     In the compounds as shown by the Formula (17) and Formula (18) above, Base represents a nucleic acid base, such as A, U, G, C or T; and R is selected from H, OH, F or a non-fluoro group described above. 
     In some embodiments, the nucleotide analogue is selected from one of an isonucleotide, an LNA, an ENA, a cET, a UNA and a GNA. In some embodiments, each non-fluoro modified nucleotide is a methoxy modified nucleotide. In the context of the present disclosure, the methoxy modified nucleotide refers to a nucleotide formed by substituting the 2′-hydroxy of the ribose group with a methoxy group. 
     In the context of the present disclosure, a “fluoro modified nucleotide”, a “2′-fluoro modified nucleotide”, a “nucleotide in which 2′-hydroxy of the ribose group is substituted with fluoro” and a “2′-fluororibosyl” have the same meaning, referring to the compound formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with fluoro, having a structure as shown by Formula (7). A “methoxy modified nucleotide”, a “2′-methoxy modified nucleotide”, a “nucleotide in which 2′-hydroxy of a ribose group is substituted with methoxy” and a “2′-methoxyribosyl” have the same meaning, referring to the compound formed by substituting the 2′-hydroxy of the ribose group of the nucleotide with methoxy, having a structure as shown by Formula (8). 
     In some embodiments, the siRNA of the present disclosure is an siRNA with the following modifications: in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 or 5, 7, 8 and 9 of the nucleotide sequence I in the sense strand are fluoro modified nucleotides, and the nucleotides at the rest of positions in the sense strand are methoxy modified nucleotides; and the nucleotides at positions 2, 6, 14 and 16 or 2, 6, 8, 9, 14 and 16 of the nucleotide sequence II in the antisense strand are fluoro modified nucleotides, and the nucleotides at the rest of positions in the antisense strand are methoxy modified nucleotides. 
     In some embodiments, the siRNA of the present disclosure is an siRNA with the following modifications: in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 5, 7, 8 and 9 of the nucleotide sequence I in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the sense strand of the siRNA are methoxy modified nucleotides; and, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 8, 9, 14 and 16 of the nucleotide sequence II in the antisense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the antisense strand of the siRNA are methoxy modified nucleotides; 
     or, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 5, 7, 8 and 9 of the nucleotide sequence I in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the sense strand of the siRNA are methoxy modified nucleotides; and, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence II in the antisense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the antisense strand of the siRNA are methoxy modified nucleotides; 
     or, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 7, 8 and 9 of the nucleotide sequence I in the sense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the sense strand of the siRNA are methoxy modified nucleotides; and, in the direction from 5′ terminal to 3′ terminal, the nucleotides at positions 2, 6, 14 and 16 of the nucleotide sequence II in the antisense strand of the siRNA are fluoro modified nucleotides, and the nucleotides at the rest of positions in the antisense strand of the siRNA are methoxy modified nucleotides. 
     In some embodiments, the siRNA provided by the present disclosure is any one of siXOa1-M1, siXOa1-M2, siXOa1-M3, siXOa2-M1, siXOa2-M2, siXOa2-M3, siXOb1-M1, siXOb1-M2, siXOb1-M3, siXOb2-M1, siXOb2-M2, siXOb2-M3, siXOc1-M1, siXOc1-M2, siXOc1-M3, siXOc2-M1, siXOc2-M2, siXOc2-M3, siXOd1-M1, siXOd1-M2, siXOd1-M3, siXOd2-M1, siXOd2-M2, siXOd2-M3, siXOe1-M1, siXOe1-M2, siXOe1-M3, siXOe2-M1, siXOe2-M2, siXOe2-M3, siXOf1-M1, siXOf1-M2, siXOf1-M3, siXOf2-M1, siXOf2-M2, siXOf2-M3, siXOg1-M1, siXOg1-M2, siXOg1-M3, siXOg2-M1, siXOg2-M2, siXOg2-M3, siXOh1-M1, siXOh1-M2, siXOh1-M3, siXOh2-M1, siXOh2-M2, siXOh2-M3, siXOi1-M1, siXOi1-M2, siXOi1-M3, siXOi2-M1, siXOi2-M2, siXOi2-M3, siXOj1-M1, siXOj1-M2, siXOj1-M3, siXOj2-M1, siXOj2-M2, siXOj2-M3, siXOk1-M1, siXOk1-M2, siXOk1-M3, siXOk2-M1, siXOk2-M2, siXOk2-M3, siXOl1-M1, siXOl1-M2, siXOl1-M3, siXOl2-M1, siXOl2-M2 and siXOl2-M3 listed in Tables 1a-1l. 
     The siRNAs with the above modifications can not only be afforded at lower costs, but also allow the ribonucleases in the blood to be less liable to cleaving the nucleic acid so as to increase the stability of the nucleic acid and enable the nucleic acid to have stronger resistance against nuclease hydrolysis. Meanwhile, the modified siRNA above has higher activity of inhibiting the target mRNA. 
     In some embodiments, at least a portion of the phosphate group in phosphate-ribose backbone of at least one single strand in the sense strand and the antisense strand of the siRNA provided by the present disclosure is a phosphate group with modified group. In some embodiments, the phosphate group with modified group is a phosphorothioate group formed by substituting at least one oxygen atom in a phosphodiester bond in the phosphate group with a sulfur atom; and in some embodiments, the phosphate group with modified group is a phosphorothioate group having a structure as shown by Formula (1): 
     
       
         
         
             
             
         
       
     
     This modification can stabilize the double-stranded structure of the siRNA, thereby maintaining high specificity and high affinity for base pairing. 
     In some embodiments, in the siRNA provided by the present disclosure, a phosphorothioate linkage exists in at least one of the following positions: the position between the first nucleotide and second nucleotides at either terminal of the sense strand or antisense strand; the position between the second and third nucleotides at either terminal of the sense strand or antisense strand; or any combination thereof In some embodiments, a phosphorothioate linkage exists at all the above positions except for 5′ terminal of the sense strand. In some embodiments, a phosphorothioate linkage exists at all the above positions except for 3′ terminal of the sense strand. In some embodiments, a phosphorothioate linkage exists in at least one of the following positions: 
     the position between the first nucleotide and the second nucleotide at 5′ terminal of the sense strand; 
     the position between the second nucleotide and the third nucleotide at 5′ terminal of the sense strand; 
     the position between the first nucleotide and the second nucleotide at 3′ terminal of the sense strand; 
     the position between the second nucleotide and the third nucleotide at 3′ terminal of the sense strand; 
     the position between the first nucleotide and the second nucleotide at 5′ terminal of the antisense strand; 
     the position between the second nucleotide and the third nucleotide at 5′ terminal of the antisense strand; 
     the position between the first nucleotide and the second nucleotide at 3′ terminal of the antisense strand; and 
     the position between the second nucleotide and the third nucleotide at 3′ terminal of the antisense strand. 
     In some embodiments, the siRNA provided by the present disclosure is any one of siXOa1-M1S, siXOa1-M2S, siXOa1-M3S, siXOa2-M1S, siXOa2-M2S, siXOa2-M3S, siXOb1-M1S, siXOb1-M2S, siXOb1-M3S, siXOb2-M1S, siXOb2-M2S, siXOb2-M3S, siXOc1-M1S, siXOc1-M2S, siXOc1-M3S, siXOc2-M1S, siXOc2-M2S, siXOc2-M3S, siXOd1-M1S, siXOd1-M2S, siXOd1-M3S, siXOd2-M1S, siXOd2-M2S, siXOd2-M3S, siXOe1-M1S, siXOe1-M2S, siXOe1-M3S, siXOe2-M1S, siXOe2-M2S, siXOe2-M3S, siXOf1-M1S, siXOf1-M2S, siXOf1-M3S, siXOf2-M1S, siXOf2-M2S, siXOf2-M3S, siXOg1-M1S, siXOg1-M2S, siXOg1-M3S, siXOg2-M1S, siXOg2-M2S, siXOg2-M3S, siXOh1-M1S, siXOh1-M2S, siXOh1-M3S, siXOh2-M1S, siXOh2-M2S, siXOh2-M3S, XOi1-M1S, siXOi1-M2S, siXOi1-M3S, siXOi2-M1S, siXOi2-M2S, siXOi2-M3S, siXOj1-M1S, siXOj1-M2S, siXOj1-M3S, siXOj2-M1S, siXOj2-M2S, siXOj2-M3S, siXOk1-M1S, siXOk1-M2S, siXOk1-M3S, siXOk2-M1S, siXOk2-M2S, siXOk2-M3S, siXOl1-M1S, siXOl1-M2S, siXOl1-M3S, siXOl2-M1S, siXOl2-M2 and siXOl2-M3S listed in Tables 1a-1l. 
     In some embodiments, the 5′-terminal nucleotide in the antisense strand of the siRNA is a 5′-phosphate nucleotide or a 5′-phosphate analogue modified nucleotide. 
     Common types of the 5′-phosphate nucleotides or 5′-phosphate analogue modified nucleotides are well known to those skilled in the art; for example, the 5′-phosphate nucleotides may have the following structure: 
     
       
         
         
             
             
         
       
     
     For another example, The chemical evolution of oligonucleotide therapies of clinical utility. Nature Biotechnology, 2017, 35(3): 238-48 written by Anastasia Khvorova and Jonathan K. Watts, disclose the following four 5′-phosphate analogue modified nucleotides: 
     
       
         
         
             
             
         
       
     
     wherein, R is selected from H, OH, methoxy or F; and Base represents a nucleic acid base selected from A, U, C, or T. 
     In some embodiments, the 5′-phosphate nucleotide is a nucleotide with 5′-phosphate modification as shown by Formula (2); the 5′-phosphate analogue modified nucleotide is a nucleotide with 5′-(E)-vinylphosphonate (E-VP) modification as shown by Formula (3) or a phosphorothioate modified nucleotide as shown by Formula (5). 
     In some embodiments, the siRNA provided by the present disclosure is any one of siXOa1-M1P1, siXOa1-M2P1, siXOa1-M3P1, siXOa2-M1P1, siXOa2-M2P1, siXOa2-M3P1, siXOa1-M1SP1, siXOa1-M2SP1, siXOa1-M3SP1, siXOa2-M1SP1, siXOa2-M2SP1, siXOa2-M3SP1, siXOb1-M1P1, siXOb1-M2P1, siXOb1-M3P1, siXOb2-M1P1, siXOb2-M2P1, siXOb2-M3P1, siXOb1-M1SP1, siXOb1-M2SP1, siXOb1-M3SP1, siXOb2-M1SP1, siXOb2-M2SP1, siXOb2-M3SP1, siXOc1-M1P1, siXOc1-M2P1, siXOc1-M3P1, siXOc2-M1P1, siXOc2-M2P1, siXOc2-M3P1, siXOc1-M1SP1, siXOc1-M2SP1, siXOc1-M3SP1, siXOc2-M1SP1, siXOc2-M2SP1, siXOc2-M3SP1, siXOd1-M1P1, siXOd1-M2P1, siXOd1-M3P1, siXOd2-M1P1, siXOd2-M2P1, siXOd2-M3P1, siXOd1-M1SP1, siXOd1-M2SP1, siXOd1-M3SP1, siXOd2-M1SP1, siXOd2-M2SP1, siXOd2-M3SP1, siXOe1-M1P1, siXOe1-M2P1, siXOe1-M3P1, siXOe2-M1P1, siXOe2-M2P1, siXOe2-M3P1, siXOe1-M1SP1, siXOe1-M2SP1, siXOe1-M3SP1, siXOe2-M1SP1, siXOe2-M2SP1, siXOe2-M3SP1, siXOf1-M1P1, siXOf1-M2P1, siXOf1-M3P1, siXOf2-M1P1, siXOf2-M2P1, siXOf2-M3P1, siXOf1-M1SP1, siXOf1-M2SP1, siXOf1-M3SP1, siXOf2-M1SP1, siXOf2-M2SP1, siXOf2-M3SP1, siXOg1-M1P1, siXOg1-M2P1, siXOg1-M3P1, siXOg2-M1P1, siXOg2-M2P1, siXOg2-M3P1, siXOg1-M1SP1, siXOg1-M2SP1, siXOg1-M3SP1, siXOg2-M1SP1, siXOg2-M2SP1, siXOg2-M3SP1, siXOh1-M1P1, siXOh1-M2P1, siXOh1-M3P1, siXOh2-M1P1, siXOh2-M2P1, siXOh2-M3P1, siXOh1-M1SP1, siXOh1-M2SP1, siXOh1-M3SP1, siXOh2-M1SP1, siXOh2-M2SP1, siXOh2-M3SP1, XOi1-M1P1, siXOi1-M2P1, siXOi1-M3P1, siXOi2-M1P1, siXOi2-M2P1, siXOi2-M3P1, siXOi1-M1SP1, siXOi1-M2SP1, siXOi1-M3SP1, siXOi2-M1SP1, siXOi2-M2SP1, siXOi2-M3SP1, siXOj1-M1P1, siXOj1-M2P1, siXOj1-M3P1, siXOj2-M1P1, siXOj2-M2P1, siXOj2-M3P1, siXOk1-M1P1, siXOk1-M2P1, siXOk1-M3P1, siXOk2-M1P1, siXOk2-M2P1, siXOk2-M3P1, siXOl1-M1P1, siXOl1-M2P1, siXOl1-M3P1, siXOl2-M1P1, siXOl2-M2P1, siXOl2-M3P1, siXOj1-M1SP1, siXOj1-M2SP1, siXOj1-M3SP1, siXOj2-M1SP1, siXOj2-M2SP1, siXOj2-M3SP1, siXOk1-M1SP1, siXOk1-M2SP1, siXOk1-M3SP1, siXOk2-M1SP1, siXOk2-M2SP1, siXOk2-M3SP1, siXOl1-M1SP1, siXOl1-M2SP1, siXOl1-M3SP1, siXOl2-M1SP1, siXOl2-M2SP1 and siXOl2-M3SP1 listed in Tables 1a-1l. 
     The inventors of the present disclosure have surprisingly found that the siRNA provided by the present disclosure has significantly enhanced plasma and lysosomal stability, and has higher inhibitory activity of target mRNA. 
     The siRNA provided by the present disclosure can be obtained by conventional methods for preparing siRNAs in the art (e.g., solid phase synthesis and liquid phase synthesis methods). 
     Commercial customization services have already been available for solid phase synthesis. Modified nucleotides can be introduced into the siRNAs of the present disclosure by using a nucleotide monomer having a corresponding modification, wherein the methods for preparing a nucleotide monomer having a corresponding modification and the methods for introducing a modified nucleotide into an siRNA are also well-known to those skilled in the art. Modified nucleotide groups may be introduced into the siRNA of the present disclosure by using a nucleotide monomer having a corresponding modification, wherein the methods for preparing the nucleotide monomer having the corresponding modification and the methods for introducing the modified nucleotide group into the siRNA are also well-known to those skilled in the art. 
     Pharmaceutical Composition 
     The present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the siRNA described above as an active ingredient, and a pharmaceutically acceptable carrier. 
     The pharmaceutically acceptable carrier may be a carrier conventionally used in the field of siRNA administration, for example, but not limited to, one or more of magnetic nanoparticles (such as Fe 3 O 4  or Fe 2 O 3 -based nanoparticle), carbon nanotubes, mesoporous silicon, calcium phosphate nanoparticles, polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly(L-lysine) (PLL), chitosan, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), poly(D&amp;L-lactic/glycolic acid) copolymer (PLGA), poly(2-aminoethyl ethylene phosphate) (PPEEA), poly(2-dimethylaminoethyl methacrylate) (PDMAEMA), and derivatives thereof. 
     In the pharmaceutical composition, there are no special requirements for the contents of the siRNA and the pharmaceutically acceptable carrier, which may be the conventional content of each component. In some embodiments, the weight ratio of the siRNA to the pharmaceutically acceptable carrier is 1:(1-500), and in some embodiments, the weight ratio above is 1:(1-50). 
     In some embodiments, the pharmaceutical composition may also comprise other pharmaceutically acceptable excipients, which may be one or more of various conventional formulations or compounds in the art. For example, the other pharmaceutically acceptable excipients may comprise at least one of a pH buffer solution, a protective agent and an osmotic pressure regulator. 
     The pH buffer solution may be a tris(hydroxymethyl) aminomethane hydrochloride buffer solution with a pH of 7.5-8.5, and/or a phosphate buffer solution with a pH of 5.5-8.5, preferably a phosphate buffer solution with a pH of 5.5-8.5. 
     The protective agent may be at least one of inositol, sorbitol, sucrose, trehalose, mannose, maltose, lactose, and glucose. The content of the protective agent may be from 0.01 wt % to 30 wt % on the basis of the total weight of the pharmaceutical composition. 
     The osmotic pressure regulator may be sodium chloride and/or potassium chloride. The content of the osmotic pressure regulator allows an osmotic pressure of the pharmaceutical composition to be 200-700 milliosmol/kg (mOsm/kg). Depending on the desired osmotic pressure, those skilled in the art can readily determine the content of the osmotic pressure regulator. 
     In some embodiments, the pharmaceutical composition may be a liquid formulation, for example, an injection solution; or a lyophilized powder for injection, which is mixed with a liquid excipient to form a liquid formulation upon administration. The liquid formulation may be administered by, but not limited to, subcutaneous, intramuscular or intravenous injection routes, and also may be administered to, but not limited to, lung by spray, or other organs (such as liver) via lung by spray. In some embodiments, the pharmaceutical composition is administered by intravenous injection. 
     In some embodiments, the pharmaceutical composition may be in the form of a liposome formulation. In some embodiments, the pharmaceutically acceptable carrier used in the liposome formulation comprises an amine-containing transfection compound (hereinafter also referred to as an organic amine), a helper lipid and/or a pegylated lipid. The organic amine, the helper lipid and the pegylated lipid may be respectively selected from one or more of the amine-containing transfection compounds or the pharmaceutically acceptable salts or derivatives thereof, the helper lipids and the pegylated lipids as described in CN103380113A (which is incorporated herein by reference in its entirety). 
     In some embodiments, the organic amine may be a compound as shown by Formula (201) as described in CN103380113A or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: 
     each of X 101  or X 102  is independently O, S, N-A or C-A, wherein A is hydrogen or a C1-C20 hydrocarbon chain; 
     each of Y 101  or Z 101  is independently C═O, C═S, S═O, CH—OH or SO 2 ; 
     each of R 101 , R 102 , R 103 , R 104 , R 105 , R 106  or R 107  is independently hydrogen; a cyclic or aliphatic, substituted or unsubstituted, branched or linear aliphatic group; a cyclic or aliphatic, substituted or unsubstituted, branched or linear heteroaliphatic group; a substituted or unsubstituted, branched or linear acyl group; a substituted or unsubstituted, branched or linear aryl, or a substituted or unsubstituted, branched or linear heteroaryl; 
     x is an integer of 1-10; 
     n is an integer of 1-3, m is an integer of 0-20, and p is 0 or 1, wherein if m=p=0, then R 102  is hydrogen, and 
     if at least one of n or m is 2, then R 103  and the nitrogen in Formula (201) form a structure as shown by Formula (202) or (203): 
     
       
         
         
             
             
         
       
     
     wherein g, e and f are each independently an integer of 1-6, “HCC” represents a hydrocarbon chain, and each *N represents a nitrogen atom shown in Formula (201). 
     In some embodiments, R 103  is a polyamine. In other embodiments, R 103  is a ketal. In some embodiments, each of R 101  and R 102  in the Formula (201) is independently any substituted or unsubstituted, branched or linear alkyl or alkenyl, wherein the alkyl or alkenyl has 3 to about 20 carbon atoms (such as 8 to about 18 carbon atoms) and 0 to 4 double bonds (such as 0 to 2 double bonds). 
     In some embodiments, if each of n and m is independently 1-3, R 103  may be any in the following Formulae (204)-(213): 
     
       
         
         
             
             
         
       
     
     wherein, in Formula (204) to Formula (213), each of g, e and f is independently an integer of 1-6; each “HCC” represents a hydrocarbon chain, and each * represents a potential attachment point of R 103  to the nitrogen atom in Formula (201), wherein each H at any * position may be replaced to realize the attachment to the nitrogen atom in Formula (201). 
     The compound as shown by (201) may be prepared as described in CN103380113A. 
     In some embodiments, the organic amine may be an organic amine as shown by Formula (214) and/or an organic amine as shown by Formula (215): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     the helper lipid is a cholesterol, a cholesterol analogue and/or a cholesterol derivative; 
     the pegylated lipid is 1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine-N-[methoxy(polyethylene glycol)]-2000. 
     In some embodiments, the molar ratio among the organic amine, the helper lipid, and the pegylated lipid in the pharmaceutical composition is (19.7-80):(19.7-80):(0.3-50); for example, the molar ratio may be (50-70):(20-40):(3-20). 
     In some embodiments, the pharmaceutical compositions formed by the siRNA of the present disclosure and the above amine-containing transfection agent have an average diameter from about 30 nm to about 200 nm, typically from about 40 nm to about 135 nm, and more typically, the average diameter of the liposome particles is from about 50 nm to about 120 nm, from about 50 nm to about 100 nm, from about 60 nm to about 90 nm, or from about 70 nm to about 90 nm, for example, the average diameter of the liposome particles is about 30, 40, 50, 60, 70, 75, 80, 85, 90, 100, 110, 120, 130, 140, 150 or 160 nm. 
     In some embodiments, in the pharmaceutical composition formed by the siRNA of the present disclosure and the above amine-containing transfection agent, the weight ratio (weight/weight ratio) of the siRNA to total lipids (e.g., the organic amine, the helper lipid and/or the pegylated lipid), ranges from about 1:1 to about 1:50, from about 1:1 to about 1:30, from about 1:3 to about 1:20, from about 1:4 to about 1:18, from about 1:5 to about 1:17, from about 1:5 to about 1:15, from about 1:5 to about 1:12, from about 1:6 to about 1:12, or from about 1:6 to about 1:10. For example, the ratio of the siRNA of the present disclosure to the total lipids is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17 or 1:18 by weight. 
     In some embodiments, the pharmaceutical composition may be marketed with each component being separate, and used in the form of a liquid formulation. In some embodiments, the pharmaceutical composition formed by the siRNA of the present disclosure and the above pharmaceutically acceptable carrier may be prepared by various known processes, except replacing the existing siRNA with the siRNA of the present disclosure. In some embodiments, the pharmaceutical composition may be prepared according to the following process. 
     The organic amines, helper lipids and pegylated lipids are suspended in alcohol at a molar ratio as described above and mixed homogeneously to yield a lipid solution; and the alcohol is used in an amount such that the resultant lipid solution is present at a total mass concentration of 2 to 25 mg/mL, e.g., 8 to 18 mg/mL. The alcohol is a pharmaceutically acceptable alcohol, such as an alcohol that is in liquid form at about room temperature, for example, one or more of ethanol, propylene glycol, benzyl alcohol, glycerol, PEG 200, PEG 300, PEG 400, and for example, ethanol. 
     The siRNA provided by the present disclosure is dissolved in a buffered salt solution to produce an aqueous solution of the siRNA. The buffered salt solution has a concentration of 0.05-0.5 M, such as 0.1-0.2 M. The pH of the buffered salt solution is adjusted to 4.0-5.5, such as 5.0-5.2. The buffered salt solution is used in an amount such that the siRNA is present at a concentration of less than 0.6 mg/ml, such as 0.2-0.4 mg/mL. The buffered salt may be one or more selected from the group consisting of soluble acetate and soluble citrate, such as sodium acetate and/or potassium acetate. 
     The lipid solution and the aqueous solution of the siRNA are mixed. The product obtained after mixing is incubated at a temperature of 40-60° C. for at least 2 minutes (e.g., 5-30 minutes) to produce an incubated lipid formulation. The volume ratio of the lipid solution to the aqueous solution of the siRNA is 1:(2-5), for example, may be 1:4. 
     The incubated liposome formulation is concentrated or diluted, purified to remove impurities, and then sterilized to obtain the pharmaceutical composition provided by the present disclosure, which has physicochemical parameters as follows: a pH of 6.5-8, an encapsulation percentage of more than 80%, a particle size of 40-200 nm, a polydispersity index of less than 0.30, and an osmotic pressure of 250-400 mOsm/kg; for example, the physicochemical parameters may be as follows: a pH of 7.2-7.6, an encapsulation percentage of more than 90%, a particle size of 60-100 nm, a polydispersity index of less than 0.20, and an osmotic pressure of 300-400 mOsm/kg. 
     The concentration or dilution step may be performed before, after or simultaneously with the step of impurity removal. The method for removing impurities may be any of various existing methods, for example, ultrafiltration using 100 KDa hollow fiber column and a phosphate buffer solution (PBS) at pH 7.4 as an ultrafiltration exchange solution and a tangential flow system. The method for sterilization may be any of various existing methods, such as filtration sterilization on a 0.22 μm filter. 
     siRNA Conjugate 
     The present disclosure provides an siRNA conjugate, wherein the siRNA conjugate comprises the siRNA above and a conjugating group conjugatively linked to the siRNA. 
     The conjugating group typically comprises at least one pharmaceutically acceptable targeting group and an optional linker. Moreover, the siRNA, the linker and the targeting group are linked in succession. In some embodiments, there are 1-6 targeting groups. In some embodiments, there are 2-4 targeting groups. The siRNA molecule may be non-covalently or covalently conjugated to the conjugating group, for example, the siRNA molecule may be covalently conjugated to the conjugating group. The conjugating site between the siRNA and the conjugating group may be at 3′-terminal or 5′-terminal of the sense strand of the siRNA, or at 5′-terminal of the antisense strand, or within the internal sequence of the siRNA. In some embodiments, the conjugating site between the siRNA and the conjugating group is at 3′ terminal of the sense strand of the siRNA. 
     In some embodiments, the conjugation group is linked to a phosphate group, a 2′-hydroxy or a base of a nucleotide. In some embodiments, the conjugation group may be linked to a 3′-hydroxy when the nucleotides are linked via a 2′-5′-phosphodiester bond. When the conjugating group is linked to a terminal of the siRNA, the conjugating group is typically linked to a phosphate group of a nucleotide; when the conjugating group is linked to an internal sequence of the siRNA, the conjugating group is typically linked to a ribose ring or a base. For specific linking modes, reference may be made to: siRNA conjugates carrying sequentially assembled trivalent N-acetylgalactosamine linked through nucleosides elicit robust gene silencing in vivo in hepatocytes. ACS Chemical biology, 2015, 10(5):1181-7, written by Muthiah Manoharan et.al. 
     In some embodiments, the siRNA and the conjugating group may be linked by an acid labile or reducible chemical bond, and these chemical bonds may be degraded under the acidic environment of cell endosomes, thereby rendering the siRNA to be in free state. For non degradable conjugating modes, the conjugating group may be linked to the sense strand of the siRNA, thereby minimizing the effect of conjugating on the activity of the siRNA. 
     In some embodiments, the pharmaceutically acceptable targeting group may be a conventionally used ligand in the field of siRNA administration, for example, the various ligands as described in WO2009082607A2, which is incorporated herein by reference in its entirety. 
     In some embodiments, the pharmaceutically acceptable targeting group may be selected from one or more of the ligands formed by the following targeting molecules or derivatives thereof: lipophilic molecules, such as cholesterol, bile acids, vitamins (such as vitamin E), lipid molecules of different chain lengths; polymers, such as polyethylene glycol; polypeptides, such as cell-penetrating peptide; aptamers; antibodies; quantum dots; saccharides, such as lactose, polylactose, mannose, galactose, and N-acetylgalactosamine (GalNAc); folate; and receptor ligands expressed in hepatic parenchymal cells, such as asialoglycoprotein, asialo-sugar residue, lipoproteins (such as high density lipoprotein, low density lipoprotein), glucagon, neurotransmitters (such as adrenaline), growth factors, transferrin and the like. 
     In some embodiments, each ligand is independently a ligand capable of binding to a cell surface receptor. In some embodiments, at least one ligand is a ligand capable of binding to a hepatocyte surface receptor. In some embodiments, at least one ligand is a ligand capable of binding to a mammalian cell surface receptor. In some embodiments, at least one ligand is a ligand capable of binding to a human cell surface receptor. In some embodiments, at least one ligand is a ligand capable of binding to a hepatic surface asialoglycoprotein receptor (ASGP-R). The types of these ligands are well-known to those skilled in the art and they typically serve the function of binding to specific receptors on the surface of the target cell, thereby mediating delivery of the siRNA linked to the ligand into the target cell. 
     In some embodiments, the pharmaceutically acceptable targeting group may be any ligand that binds to asialoglycoprotein receptors (ASGP-R) on the surface of mammalian hepatocytes. In one embodiment, each ligand is independently an asialoglycoprotein, such as asialoorosomucoid (ASOR) or asialofetuin (ASF). In some embodiments, the ligand is a saccharide or a saccharide derivative. 
     In some embodiments, at least one ligand is a saccharide. In some embodiments, each ligand is a saccharide. In some embodiments, at least one ligand is a monosaccharide, polysaccharide, modified monosaccharide, modified polysaccharide, or saccharide derivative. In some embodiments, at least one ligand may be a monosaccharide, disaccharide or trisaccharide. In some embodiments, at least one ligand is a modified saccharide. In some embodiments, each ligand is a modified saccharide. In some embodiments, each ligand is independently selected from the group consisting of polysaccharides, modified polysaccharides, monosaccharides, modified monosaccharides, polysaccharide derivatives or monosaccharide derivatives. In some embodiments, each ligand or at least one ligand is selected from the group consisting of the following saccharides: glucose and derivative thereof, mannose and derivative thereof, galactose and derivative thereof, xylose and derivative thereof, ribose and derivative thereof, fucose and derivative thereof, lactose and derivative thereof, maltose and derivative thereof, arabinose and derivative thereof, fructose and derivative thereof, and sialic acid. 
     In some embodiments, each ligand may be independently selected from one of D-mannopyranose, L-mannopyranose, D-arabinose, D-xylofuranose, L-xylofuranose, D-glucose, L-glucose, D-galactose, L-galactose, α-D-mannofuranose, β-D-mannofuranose, α-D-mannopyranose, β-D-mannopyranose, α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, β-D-glucofuranose, α-D-fructofuranose, α-D-fructopyranose, α-D-galactopyranose, β-D-galactopyranose, α-D-galactofuranose, β-D-galactofuranose, glucosamine, sialic acid, galactosamine, N-acetylgalactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, N-isobutyrylgalactosamine, 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-β-D-glucopyranose, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose, N-glycolyl-α-neuraminic acid, 5-thio-β-D-glucofuranose, methyl 2,3,4-tris-O-acetyl-1-thio-6-O-trityl-α-D-glucofuranose, 4-thio-β-D-galactopyranose, ethyl 3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-glucoheptopyranoside, 2,5-anhydro-D-allononitrile, ribose, D-ribose, D-4-thioribose, L-ribose, or L-4-thioribose. Other ligand selections may be found, for example, in the disclosure of CN105378082A, which is incorporated herein by reference in its entirety. 
     In some embodiments, the pharmaceutically acceptable targeting group in the siRNA conjugate may be galactose or N-acetylgalactosamine, wherein the galactose or N-acetylgalactosamine molecules may be monovalent, bivalent, trivalent and tetravalent. It should be understood that the terms monovalent, bivalent, trivalent and tetravalent described herein respectively mean that the molar ratio of the siRNA molecule to the galactose or N-acetylgalactosamine molecule in the siRNA conjugate is 1:1, 1:2, 1:3 or 1:4, wherein the siRNA conjugate is formed from the siRNA molecule and the conjugating group containing galactose or N-acetylgalactosamine as the targeting group. In some embodiments, the pharmaceutically acceptable targeting group is N-acetylgalactosamine. In some embodiments, when the siRNA of the present disclosure is conjugated to a conjugation group comprising N-acetylgalactosamine, the N-acetylgalactosamine molecule is trivalent or tetravalent. In some embodiments, when the siRNA of the present disclosure is conjugated to a conjugating group containing N-acetylgalactosamine, the N-acetylgalactosamine molecule is trivalent. 
     The targeting group may be linked to the siRNA molecule via an appropriate linker, and the appropriate linker may be selected by those skilled in the art according to the specific type of the targeting group. The types of these linkers and targeting groups and the linking modes with the siRNA may be found in the disclosure of W2015006740A2, which is incorporated herein by reference in its entirety. 
     In some embodiments, when the targeting group is N-acetylgalactosamine, an appropriate linker may be a structure as shown by Formula (301): 
     
       
         
         
             
             
         
       
     
     wherein, 
     k is an integer of 1-3; and 
     L A  is an amide bond-comprising chain moiety that has a structure as shown by Formula (302), each L A  being respectively linked to the targeting group and the L C  moiety through an ether bond at two terminals thereof: 
     
       
         
         
             
             
         
       
     
     L B  is an N-acylpyrrolidine-comprising chain moiety that has a structure as shown by Formula (303), the chain moiety having a carbonyl at one terminal thereof and being linked to the L C  moiety through an amide bond, and having an oxy-group at the other terminal thereof and being linked to the siRNA via a phosphoester bond: 
     
       
         
         
             
             
         
       
     
     L C  is a bivalent to tetravalent linking group based on hydroxymethyl aminomethane, dihydroxymethyl aminomethane or trihydroxymethyl aminomethane, the L C  being linked to each of the L A  moieties through an ether bond via an oxygen atom, and being linked to the L B  moiety through an amide bond via a nitrogen atom. 
     In some embodiments, when n=3 and L C  is a tetravalent linking group based on trihydroxymethyl aminomethane, the siRNA conjugate formed by linking an N-acetylgalactosamine molecule with an siRNA molecule via -(L A ) 3 -trihydroxymethyl aminomethane-L B - as a linker has a structure as shown by Formula (304): 
     
       
         
         
             
             
         
       
     
     wherein the double helix structure represents an siRNA. 
     Likewise, the conjugating site between the siRNA and the conjugating group nay be at the 3′-terminal or 5′-terminal of the sense strand of the siRNA, or at the 5′-terminal of the antisense strand, or within the internal sequence of the siRNA. 
     In some embodiments, the 3′-terminal of the sense strand of the siRNA of the present disclosure is covalently conjugated to three N-acetylgalactosamine (GalNAc) molecules via a linker -(L A ) 3 -trihydroxymethyl aminomethane-L B - to obtain an siRNA conjugate in which the molar ratio of the siRNA molecule to the GaINAc molecule is 1:3, which may also be hereinafter referred to as (GaINAc) 3 -siRNA), and the siRNA conjugate has a structure as shown by Formula (305): 
     
       
         
         
             
             
         
       
     
     wherein the double helix structure represents an siRNA; and the linker is linked to the 3′ terminal of the sense strand of the siRNA. 
     In some embodiments, when the targeting group is N-acetylgalactosamine, an appropriate linker may be a structure as shown by Formula (306): 
     
       
         
         
             
             
         
       
     
     wherein, 
     l is an integer of 0-3; 
     # represents a site linked to the targeting group via an ether bond on the linker; and # represents a site linked to the siRNA via a phosphoester bond on the linker. 
     In some embodiments, when l=2, the siRNA conjugate has a structure as shown by Formula (307): 
     
       
         
         
             
             
         
       
     
     wherein the double helix structure represents an siRNA; and the linker is linked to the 3′ terminal of the sense strand of the siRNA. 
     The above conjugates may be synthesized according to the methods described in detail in the prior art. For example, W02015006740A2 describes the method of preparing various conjugates in detail. The siRNA conjugate of the present disclosure may be obtained by methods well known to those skilled in the art. As another example, W02014025805A1 describes the preparation method of the conjugate having a structure as shown by Formula (305). Rajeev et al., describes the preparation method of the conjugate having a structure as shown by Formula (307) in Chem Bio Chem 2015, 16, 903-908. 
     In some embodiments, the siRNA conjugate has a structure as shown by Formula (308): 
     
       
         
         
             
             
         
       
     
     wherein: 
     n1 is an integer of 1-3, and n3 is an integer of 0-4; 
     m1, m2, and m3 is independently an integer of 2-10; 
     R 10 , R 11 , R 12 , R 13 , R 14  or R 15  is independently H or selected from the group consisting of C 1 -C 10  alkyl, C 1 -C 10  haloalkyl and C 1 -C 10  alkoxy; and 
     R 3  is a group having a structure as shown by Formula A59: 
     
       
         
         
             
             
         
       
     
     wherein, E 1  is OH, SH or BH 2 , and Nu is the siRNA of the present disclosure; 
     R 2  is a linear alkylene of 1-20 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with any one or more of the group consisting of: C(O), NH, O, S, CH═N, S(O) 2 , C 2 -C 10  alkeylene, C 2 -C 10  alkynylene, C 6 -C 10  arylene, C 3 -C 18  heterocyclylene, and C 5 -C 10  heteroarylene; and wherein R 2  is optionally substituted by any one or more of the group consisting of: C 1 -C 10  alkyl, C 6 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  haloalkyl, —OC 1 —C 10  alkyl, —OC 1 —C 10  alkylphenyl, —C 1 -C 10  alkyl-OH, —OC 1 —C 10  haloalkyl, —SC 1 —C 10  alkyl, —SC 1 —C 10  alkylphenyl, —C 1 -C 10  alkyl-SH, —SC 1 —C 10  haloalkyl, halo substituent, —OH, —SH, —NH 2 , —C 1 -C 10  alkyl-NH 2 , —N(C 1 -C 10  alkyl)(C 1 -C 10  alkyl), —NH(C 1 -C 10  alkyl), —N(C 1 -C 10  alkyl)(C 1 -C 10  alkylphenyl), —NH(C 1 -C 10  alkylphenyl), cyano, nitro, —CO 2 H, —C(O)O(C 1 -C 10  alkyl), —CON(C 1 -C 10  alkyl)(C 1 -C 10  alkyl), —CONH(C 1 -C 10  alkyl), —CONH 2 , —NHC(O)(C 1 -C 10  alkyl), —NHC(O)(phenyl), —N(C 1 -C 10  alkyl)C(O)(C 1 -C 10  alkyl), —N(C 1 -C 10  alkyl)C(O)(phenyl), —C(O)C 1 -C 10  alkyl, —C(O)C 1 -C 10  alkylphenyl, —C(O)C 1 -C 10  haloalkyl, —OC(O)C 1 -C 10  alkyl, —SO 2 (C 1 -C 10  alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 10  haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 10  alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 10  alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 10  haloalkyl); and 
     each L 1  is a linear alkylene of 1-70 carbon atoms in length, wherein one or more carbon atoms are optionally replaced with any one or more of the group consisting of: C(O), NH, O, S, CH═N, S(O) 2 , C 2 -C 10  alkeylene, C 2 -C 10  alkynylene, C 6 -C 10  arylene, C 3 -C 18  heterocyclylene, and C 5 -C 10  heteroarylene; and wherein L 1  is optionally substituted by any one or more of the group consisting of: C 1 -C 10  alkyl, C 6 -C 10  aryl, C 5 -C 10  heteroaryl, haloalkyl, —OC 1 —C 10  alkyl, —OC 1 —C 10  alkylphenyl, —C 1 -C 10  alkyl-OH, —OC 1 —C 10  haloalkyl, —SC 1 —C 10  alkyl, —SC 1 —C 10  alkylphenyl, —C 1 -C 10 alkyl-SH, —SC 1 —C 10  haloalkyl, halo substituent, —OH, —SH, —NH 2 , —C 1 -C 10  alkyl-NH 2 , —N(C 1 -C 10  alkyl)(C 1 -C 10  alkyl), —NH(C 1 -C 10  alkyl), —N(C 1 -C 10  alkyl)(C 1 -C 10  alkylphenyl), —NH(C 1 -C 10  alkylphenyl), cyano, nitro, —CO 2 H, —C(O)O(C 1 -C 10  alkyl), —CON(C 1 -C 10  alkyl)(C 1 -C 10  alkyl), —CONH(C 1 -C 10  alkyl), —CONH 2 , —NHC(O)(C 1 -C 10  alkyl), —NHC(O)(phenyl), —N(C 1 -C 10  alkyl)C(O)(C 1 -C 10  alkyl), —N(C 1 -C 10  alkyl)C(O)(phenyl), —C(O)C 1 -C 10  alkyl, —C(O)C 1 -C 10  alkylphenyl, —C(O)C 1 -C 10  haloalkyl, —OC(O)C 1 -C 10  alkyl, —SO 2 (C 1 -C 10  alkyl), —SO 2 (phenyl), —SO 2 (C 1 -C 10  haloalkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 10  alkyl), —SO 2 NH(phenyl), —NHSO 2 (C 1 -C 10  alkyl), —NHSO 2 (phenyl), and —NHSO 2 (C 1 -C 10  haloalkyl). 
     In some embodiments, L 1  may be selected from the group consisting of groups A1-A26 and any combination thereof, wherein the structures and definitions of A1-A26 are as follows: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein, j1 is an integer of 1-20; and j2 is an integer of 1-20; 
     R′ is a C 1 -C 10  alkyl; and 
     Ra is selected from the group consisting of groups A27-A45 and any combinations thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Rb is a C 1 -C 10  alkyl; and   represents a site where the group is covalently linked. 
     Those skilled in the art would understand that, though L 1  is defined as a linear alkylene for convenience, but it may not be a linear group or be named differently, such as an amine or alkenyl produced by the above replacement and/or substitution. For the purpose of the present disclosure, the length of L 1  is the number of the atoms in the chain connecting the two attaching points. For this purpose, a ring obtained by replacement of a carbon atom of the linear alkylene, such as a heterocyclylene or heteroarylene, is counted as one atom. 
     M 1  represents a targeting group, of which the definitions and options are the same as those described above. In some embodiments, each M 1  is independently selected from one of the ligands that have affinity to the asialoglycoprotein receptor on the surface of mammalian hepatocytes. 
     When M 1  is a ligand that has affinity to the asialoglycoprotein receptor on the surface of mammalian hepatocytes, in some embodiments, nl may be an integer of 1-3, and n3 may be an integer of 0-4 to ensure that the number of the M 1  targeting group in the siRNA conjugate may be at least 2. In some embodiments, n1+n3≥2, such that the number of the M 1  targeting group in the conjugate may be at least 3, thereby allowing the M 1  targeting group to more conveniently bind to the asialoglycoprotein receptor on the surface of hepatocytes, which may facilitate the endocytosis of the siRNA conjugate into cells. Experiments have shown that when the number of the M 1  targeting group is greater than 3, the ease of binding the M 1  targeting group to the asialoglycoprotein receptor on the surface of hepatocytes is not significantly increased. Therefore, in view of various aspects such as synthesis convenience, structure/process costs and delivery efficiency, in some embodiments, n1 is an integer of 1-2, n3 is an integer of 0-1, and n+n3=2-3. 
     In some embodiments, when m1, m2, or m3 is independently selected from selected from an integer of 2-10, the steric mutual positions among a plurality of M 1  targeting groups may be fit for binding the Mi targeting groups to the asialoglycoprotein receptor on the surface of hepatocytes. In order to make the siRNA conjugate provided by the present disclosure have simpler structure, easier synthesis and/or reduced cost, in some embodiments, m1, m2 and m3 are independently an integer of 2-5, and in some embodiments, m1=m2=m3. 
     Those skilled in the art would understand that when R 10 , R 11 , R 12 , R 13 , R 14 , or R 15  is each independently selected from one of H, C 1 -C 10  alkyl, C 1 -C 10  haloalkyl, and C 1 -C 10  alkoxy, they would not change the properties of the siRNA conjugate of the present disclosure and could all achieve the purpose of the present disclosure. In some embodiments, R 10 , R 11 , R 12 , R 13 , R 14 , or R 15  is each independently selected from selected from H, methyl or ethyl. In some embodiments, R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are all H. 
     R 3  is a group having the structure as shown by Formula A59, wherein E 1  is OH, SH or BH 2 , and considering the availability of starting materials, in some embodiments, E 1  is OH or SH. 
     R 2  is selected to achieve the linkage between the group as shown by Formula A59 and the N atom on a nitrogenous backbone. In the context of the present disclosure, the “nitrogenous backbone” refers to a chain structure in which the carbon atoms attached to R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  and the N atoms are linked to each other. Therefore, R 2  may be any linking group capable of attaching the group as shown by Formula A59 to the N atom on a nitrogenous backbone by suitable means. In some embodiments, in the case where the siRNA conjugate as shown by Formula (308) of the present disclosure is prepared by a solid phase synthesis process, R 2  group needs to have both a site linking to the N atom on the nitrogenous backbone and a site linking to the P atom in R 3 . In some embodiments, in R 2 , the site linking to the N atom on the nitrogenous backbone forms an amide bond with the N atom, and the site linking to the P atom in R 3  forms a phosphoester bond with the P atom. In some embodiments, R 2  may be B5, B6, B5′ or B6′: 
     
       
         
         
             
             
         
       
     
     wherein,   represents a site where the group is covalently linked. 
     A value range of q 2  may be an integer of 1-10; and in some embodiments, q 2  is an integer of 1-5. 
     L 1  is used to link the M 1  targeting group to the N atom on the nitrogenous backbone, thereby providing liver targeting function for the siRNA conjugate as shown by Formula (308). In some embodiments, L 1  is selected from the connection combinations of one or more of groups as shown by Formulae A1-A26. In some embodiments, L 1  is selected from the connection combinations of one or more of A1, A4, A5, A6, A8, A10, A11, and A13. In some embodiments, L 1  is selected from the connection combinations of at least two of A1, A4, A8, A10, and A11. In some embodiments, L 1  is selected from the connection combinations of at least two of A1, A8, and A10. 
     In some embodiments, the length of L 1  may be 3-25 atoms, 3-20 atoms, 4-15 atoms or 5-12 atoms. In some embodiments, the length of L 1  is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60 atoms. 
     In some embodiments, j1 is an integer of 2-10, and in some embodiments, j1 is an integer of 3-5. In some embodiments, j2 is an integer of 2-10, and in some embodiments, j2 is an integer of 3-5. R′ is a C 1 -C 4  alkyl, and in some embodiments, R′ is one of methyl, ethyl, and isopropyl. Ra is one of A27, A28, A29, A30, and A31, and in some embodiments, Ra is A27 or A28. Rb is a C1-C5 alkyl, and in some embodiments, Rb is one of methyl, ethyl, isopropyl, and butyl. In some embodiments, j1, j2, R′, Ra, and Rb of Formulae A1-A26 are respectively selected to achieve the linkage between the M 1  targeting group and the N atom on the nitrogenous backbone, and to make the steric mutual position among the M 1  targeting group more suitable for binding the M 1  targeting group to the asialoglycoprotein receptor on the surface of hepatocytes. 
     In some embodiments, the siRNA conjugate has a structure as shown by Formula (403), (404), (405), (406), (407), (408), (409), (410), (411), (412), (413), (414), (415), (416), (417), (418), (419), (420), (421) or (422): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, the P atom in Formula A59 may be linked to any possible position in the siRNA sequence, for example, the P atom in Formula A59 may be linked to any nucleotide in the sense strand or the antisense strand of the siRNA. In some embodiments, the P atom in Formula A59 is linked to any nucleotide in the sense strand of the siRNA. In some embodiments, the P atom in Formula A59 is linked to a terminal of the sense strand or the antisense strand of the siRNA. In some embodiments, the P atom in Formula A59 is linked to a terminal of the sense strand of the siRNA. The terminal refers to the first 4 nucleotides counted from one terminal of the sense strand or antisense strand. In some embodiments, the P atom in Formula A59 is linked to the terminal of the sense strand or the antisense strand of the siRNA. In some embodiments, the P atom in Formula A59 is linked to 3′ terminal of the sense strand of the siRNA. In the case where the P atom in Formula A59 is linked to the above position in the sense strand of the siRNA, after entering into cells, the siRNA conjugate as shown by Formula (308) can release a separate antisense strand of the siRNA during unwinding, thereby blocking the translation of the XO mRNA into protein and inhibiting the expression of XO gene. 
     In some embodiments, the P atom in Formula A59 may be linked to any possible position of a nucleotide in the siRNA, for example, to position 5′, 2′ or 3′, or to the base of the nucleotide. In some embodiments, the P atom in Formula A59 may be linked to position 2′, 3′, or 5′ of a nucleotide in the siRNA by forming a phosphodiester bond. In some embodiments, the P atom in Formula A59 is linked to an oxygen atom formed by deprotonation of 3′ hydroxy of the nucleotide at 3′terminal of the sense strand of the siRNA (in this time, the P atom in Formula A59 may also be regarded as a P atom in a phosphate group contained in the siRNA), or the P atom in Formula A59 is linked to a nucleotide by substituting a hydrogen atom in 2′-hydroxy of a nucleotide of the sense strand of the siRNA, or the P atom in Formula A59 is linked to a nucleotide by substituting hydrogen in 5′-hydroxy of the nucleotide at 5′ terminal of the sense strand of the siRNA. 
     The inventors of the present disclosure have surprisingly found that the siRNA conjugate of the present disclosure has significantly improved stability in plasma and low off-target effect, and also shows higher silencing activity against XO mRNA. In some embodiments, the siRNA of the present disclosure may be one of the siRNAs shown in Tables 1a-1l. The siRNA conjugates containing these siRNA show higher silencing activity against XO mRNA. 
     
       
         
           
               
             
               
                 TABLE 1a 
               
             
            
               
                   
               
               
                 The first siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOa1 
                  9 
                 GAGAUGAAGUUCAAGAAUA 
               
               
                   
                 10 
                 UAUUCUUGAACUUCAUCUCAA 
               
               
                   
               
               
                 siXOa2 
                 11 
                 UUGAGAUGAAGUUCAAGAAUA 
               
               
                   
                 12 
                 UAUUCUUGAACUUCAUCUCAAUG 
               
               
                   
               
               
                 siXOa1- 
                 13 
                 GmAmGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M1 
                 14 
                 UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
               
               
                 siXOa1- 
                 15 
                 GmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2 
                 16 
                 UmAfUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
               
               
                 siXOa1- 
                 17 
                 GmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3 
                 18 
                 UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
               
               
                 siXOa2- 
                 19 
                 UmUmGmAmGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M1 
                   
                 m 
               
               
                   
                 20 
                 UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOa2- 
                 21 
                 UmUmGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2 
                 22 
                 UmAfUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmAmU 
               
               
                   
                   
                 mGm 
               
               
                   
               
               
                 siXOa2- 
                 23 
                 UmUmGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3 
                 24 
                 UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOa1- 
                 25 
                 GmsAmsGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M1S 
                 26 
                 UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmsAms 
               
               
                   
                   
                 Am 
               
               
                   
               
               
                 siXOa1- 
                 27 
                 GmsAmsGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2S 
                 28 
                 UmsAfsUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmsAmsA 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOa1- 
                 29 
                 GmsAmsGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3S 
                 30 
                 UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmsAms 
               
               
                   
                   
                 Am 
               
               
                   
               
               
                 siXOa2- 
                 31 
                 UmsUmsGmAmGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUm 
               
               
                 M1S 
                   
                 Am 
               
               
                   
                 32 
                 UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOa2- 
                 33 
                 UmsUmsGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 34 
                 UmsAfsUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmAms 
               
               
                   
                   
                 UmsGm 
               
               
                   
               
               
                 siXOa2- 
                 35 
                 UmsUmsGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 36 
                 UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOa1- 
                 37 
                 GmAmGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M1P1 
                 38 
                 P1UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOa1- 
                 39 
                 GmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2P1 
                 40 
                 P1UmAfUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
               
               
                 siXOa1- 
                 41 
                 GmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3P1 
                 42 
                 P1UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOa2- 
                 43 
                 UmUmGmAmGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 44 
                 PlUmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 mUmGm 
               
               
                   
               
               
                 siXOa2- 
                 45 
                 UmUmGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2P1 
                 46 
                 P1UmAfUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmAm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOa2- 
                 47 
                 UmUmGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3P1 
                 48 
                 P1UmAfUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 mUmGm 
               
               
                   
               
               
                 siXOa1- 
                 49 
                 GmsAmsGmAmUmGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M1SP1 
                 50 
                 P1UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmsA 
               
               
                   
                   
                 msAm 
               
               
                   
               
               
                 siXOa1- 
                 51 
                 GmsAmsGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M2SP1 
                 52 
                 P1UmsAfsUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmsAms 
               
               
                   
                   
                 Am 
               
               
                   
               
               
                 siXOa1- 
                 53 
                 GmsAmsGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmAm 
               
               
                 M3SP1 
                 54 
                 P1UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmsA 
               
               
                   
                   
                 msAm 
               
               
                   
               
               
                 siXOa2- 
                 55 
                 UmsUmsGmAmGmAmUmGmAfAfGfUmUmCmAmAm GmAmAmUm 
               
               
                 M1SP1 
                   
                 Am 
               
               
                   
                 56 
                 P1UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAm 
               
               
                   
                   
                 AmsUmsGm 
               
               
                   
               
               
                 siXOa2- 
                 57 
                 UmsUmsGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 58 
                 P1UmsAfsUmUmCmUfUmGfAfAmCmUmUmCfAmUfCmUmCmAmA 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOa2- 
                 59 
                 UmsUmsGmAmGmAmUfGmAfAfGfUmUmCmAmAmGmAmAmUmA 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 60 
                 P1UmsAfsUmUmCmUfUmGmAmAmCmUmUmCfAmUfCmUmCmAm 
               
               
                   
                   
                 AmsUmsGm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1b 
               
             
            
               
                   
               
               
                 The second siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOb1 
                  69 
                 CAUAACUGGAAUUUGUAAU 
               
               
                   
                  70 
                 AUUACAAAUUCCAGUUAUGUU 
               
               
                   
               
               
                 siXOb2 
                  71 
                 AACAUAACUGGAAUUUGUAAU 
               
               
                   
                  72 
                 AUUACAAAUUCCAGUUAUGUUAC 
               
               
                   
               
               
                 siXOb1- 
                  73 
                 CmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M1 
                  74 
                 AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
               
               
                 siXOb1- 
                  75 
                 CmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2 
                  76 
                 AmUfUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
               
               
                 siXOb1- 
                  77 
                 CmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3 
                  78 
                 AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
               
               
                 siXOb2- 
                  79 
                 AmAmCmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                  80 
                 AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOb2 
                  81 
                 AmAmCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2 
                  82 
                 AmUfUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmUmA 
               
               
                   
                   
                 mCm 
               
               
                   
               
               
                 siXOb2- 
                  83 
                 AmAmCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3 
                  84 
                 AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOb1- 
                  85 
                 CmsAmsUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M1S 
                  86 
                 AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOb1- 
                  87 
                 CmsAmsUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2S 
                  88 
                 AmsUfsUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmsUmsU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOb1- 
                  89 
                 CmsAmsUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3S 
                  90 
                 AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOb2- 
                  91 
                 AmsAmsCmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                  92 
                 AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmU 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOb2- 
                  93 
                 AmsAmsCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                  94 
                 AmsUfsUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
                   
                 sAmsCm 
               
               
                   
               
               
                 siXOb2- 
                  95 
                 AmsAmsCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                  96 
                 AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUmU 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOb1- 
                  97 
                 CmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M1P1 
                  98 
                 P1AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOb1- 
                  99 
                 CmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2P1 
                 100 
                 P1AmUfUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
               
               
                 siXOb1- 
                 101 
                 CmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3P1 
                 102 
                 P1AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOb2- 
                 103 
                 AmAmCmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 104 
                 P1AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUm 
               
               
                   
                   
                 UmAmCm 
               
               
                   
               
               
                 siXOb2- 
                 105 
                 AmAmCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2P1 
                 106 
                 P1AmUfUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmUm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOb2- 
                 107 
                 AmAmCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3P1 
                 108 
                 P1AmUfUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmUm 
               
               
                   
                   
                 UmAmCm 
               
               
                   
               
               
                 siXOb1- 
                 109 
                 CmsAmsUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M1SP1 
                 110 
                 P1AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmsU 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOb1- 
                 111 
                 CmsAmsUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M2SP1 
                 112 
                 P1AmsUfsUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOb1- 
                 113 
                 CmsAmsUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmUm 
               
               
                 M3SP1 
                 114 
                 P1AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmsU 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOb2- 
                 115 
                 AmsAmsCmAmUmAmAmCmUfGfGfAmAmUmUmUmGmUmAmAm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 116 
                 P1AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmU 
               
               
                   
                   
                 mUmsAmsCm 
               
               
                   
               
               
                 siXOb2- 
                 117 
                 AmsAmsCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 118 
                 P1AmsUfsUmAmCmAfAmAfUfUmCmCmAmGfUmUfAmUmGmUmU 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOb2- 
                 119 
                 AmsAmsCmAmUmAmAfCmUfGfGfAmAmUmUmUmGmUmAmAmU 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 120 
                 P1AmsUfsUmAmCmAfAmAmUmUmCmCmAmGfUmUfAmUmGmU 
               
               
                   
                   
                 mUmsAmsCm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1c 
               
             
            
               
                   
               
               
                 The third siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOc1 
                 129 
                 CAUUAUCACAAUUGAGGAU 
               
               
                   
                 130 
                 AUCCUCAAUUGUGAUAAUGGC 
               
               
                   
               
               
                 siXOc2 
                 131 
                 GCCAUUAUCACAAUUGAGGAU 
               
               
                   
                 132 
                 AUCCUCAAUUGUGAUAAUGGCUG 
               
               
                   
               
               
                 siXOc1- 
                 133 
                 CmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M1 
                 134 
                 AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
               
               
                 siXOc1- 
                 135 
                 CmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2 
                 136 
                 AmUfCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
               
               
                 siXOc1- 
                 137 
                 CmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3 
                 138 
                 AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
               
               
                 siXOc2- 
                 139 
                 GmCmCmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                 140 
                 AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOc2- 
                 141 
                 GmCmCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2 
                 142 
                 AmUfCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmCmU 
               
               
                   
                   
                 mGm 
               
               
                   
               
               
                 siXOc2- 
                 143 
                 GmCmCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3 
                 144 
                 AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOc1- 
                 145 
                 CmsAmsUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M1S 
                 146 
                 AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmsGms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOc1- 
                 147 
                 CmsAmsUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2S 
                 148 
                 AmsUfsCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmsGmsC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOc1- 
                 149 
                 CmsAmsUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3S 
                 150 
                 AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmsGms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOc2- 
                 151 
                 GmsCmsCmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                 152 
                 AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOc2- 
                 153 
                 GmsCmsCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 154 
                 AmsUfsCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmCms 
               
               
                   
                   
                 UmsGm 
               
               
                   
               
               
                 siXOc2- 
                 155 
                 GmsCmsCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 156 
                 AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOc1- 
                 157 
                 CmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M1P1 
                 158 
                 P1AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOc1- 
                 159 
                 CmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2P1 
                 160 
                 P1AmUfCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
               
               
                 siXOc1- 
                 161 
                 CmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3P1 
                 162 
                 P1AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOc2- 
                 163 
                 GmCmCmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 164 
                 P1AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 mUmGm 
               
               
                   
               
               
                 siXOc2- 
                 165 
                 GmCmCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2P1 
                 166 
                 P1AmUfCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmCm 
               
               
                   
                   
                 UmGm 
               
               
                   
               
               
                 siXOc2- 
                 167 
                 GmCmCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3P1 
                 168 
                 P1AmUfCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 mUmGm 
               
               
                   
               
               
                 siXOc1- 
                 169 
                 CmsAmsUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M1SP1 
                 170 
                 P1AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmsG 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOc1- 
                 171 
                 CmsAmsUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M2SP1 
                 172 
                 P1AmsUfsCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmsGms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOc1- 
                 173 
                 CmsAmsUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmUm 
               
               
                 M3SP1 
                 174 
                 P1AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmsG 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOc2- 
                 175 
                 GmsCmsCmAmUmUmAmUmCfAfCfAmAmUmUmGmAmGmGmAm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 176 
                 P1AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmG 
               
               
                   
                   
                 mCmsUmsGm 
               
               
                   
               
               
                 siXOc2- 
                 177 
                 GmsCmsCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 178 
                 P1AmsUfsCmCmUmCfAmAfUfUmGmUmGmAfUmAfAmUmGmGmC 
               
               
                   
                   
                 msUmsGm 
               
               
                   
               
               
                 siXOc2- 
                 179 
                 GmsCmsCmAmUmUmAfUmCfAfCfAmAmUmUmGmAmGmGmAmU 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 180 
                 P1AmsUfsCmCmUmCfAmAmUmUmGmUmGmAfUmAfAmUmGmG 
               
               
                   
                   
                 mCmsUmsGm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1d 
               
             
            
               
                   
               
               
                 The fourth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOd1 
                 189 
                 GGAUCUCUCUCAGAGUAUU 
               
               
                   
                 190 
                 AAUACUCUGAGAGAGAUCCUG 
               
               
                   
               
               
                 siXOd2 
                 191 
                 CAGGAUCUCUCUCAGAGUAUU 
               
               
                   
                 192 
                 AAUACUCUGAGAGAGAUCCUGGG 
               
               
                   
               
               
                 siXOd1- 
                 193 
                 GmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M1 
                 194 
                 AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
               
               
                 siXOd1- 
                 195 
                 GmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2 
                 196 
                 AmAfUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
               
               
                 siXOd1- 
                 197 
                 GmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3 
                 198 
                 AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
               
               
                 siXOd2- 
                 199 
                 CmAmGmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                 200 
                 AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
                   
                 GmGm 
               
               
                   
               
               
                 siXOd2- 
                 201 
                 CmAmGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2 
                 202 
                 AmAfUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmGmG 
               
               
                   
                   
                 mGm 
               
               
                   
               
               
                 siXOd2- 
                 203 
                 CmAmGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3 
                 204 
                 AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
                   
                 GmGm 
               
               
                   
               
               
                 siXOd1- 
                 205 
                 GmsGmsAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M1S 
                 206 
                 AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmsUms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOd1- 
                 207 
                 GmsGmsAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2S 
                 208 
                 AmsAfsUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmsUmsG 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOd1- 
                 209 
                 GmsGmsAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3S 
                 210 
                 AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmsUms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOd2- 
                 211 
                 CmsAmsGmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                 212 
                 AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 msGmsGm 
               
               
                   
               
               
                 siXOd2- 
                 213 
                 CmsAmsGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 214 
                 AmsAfsUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmGms 
               
               
                   
                   
                 GmsGm 
               
               
                   
               
               
                 siXOd2- 
                 215 
                 CmsAmsGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 216 
                 AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 msGmsGm 
               
               
                   
               
               
                 siXOd1- 
                 217 
                 GmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M1P1 
                 218 
                 P1AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOd1- 
                 219 
                 GmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2P1 
                 220 
                 P1AmAfUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
               
               
                 siXOd1- 
                 221 
                 GmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3P1 
                 222 
                 P1AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOd2- 
                 223 
                 CmAmGmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 224 
                 P1AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 mGmGm 
               
               
                   
               
               
                 siXOd2- 
                 225 
                 CmAmGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2P1 
                 226 
                 P1AmAfUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmGm 
               
               
                   
                   
                 GmGm 
               
               
                   
               
               
                 siXOd2- 
                 227 
                 CmAmGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3P1 
                 228 
                 P1AmAfUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 mGmGm 
               
               
                   
               
               
                 siXOd1- 
                 229 
                 GmsGmsAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M1SP1 
                 230 
                 P1AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmsU 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOd1- 
                 231 
                 GmsGmsAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M2SP1 
                 232 
                 P1AmsAfsUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmsUms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOd1- 
                 233 
                 GmsGmsAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmUm 
               
               
                 M3SP1 
                 234 
                 P1AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmsU 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOd2- 
                 235 
                 CmsAmsGmGmAmUmCmUmCfUfCfUmCmAmGmAmGmUmAmUm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 236 
                 P1AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmU 
               
               
                   
                   
                 mGmsGmsGm 
               
               
                   
               
               
                 siXOd2- 
                 237 
                 CmsAmsGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M2SP1  
                 m 
                   
               
               
                   
                 238 
                 P1AmsAfsUmAmCmUfCmUfGfAmGmAmGmAfGmAfUmCmCmUmG 
               
               
                   
                   
                 msGmsGm 
               
               
                   
               
               
                 siXOd2- 
                 239 
                 CmsAmsGmGmAmUmCfUmCfUfCfUmCmAmGmAmGmUmAmUmU 
               
               
                 M3SP1  
                 m 
                   
               
               
                   
                 240 
                 P1AmsAfsUmAmCmUfCmUmGmAmGmAmGmAfGmAfUmCmCmU 
               
               
                   
                   
                 mGmsGmsGm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1e 
               
             
            
               
                   
               
               
                 The fifth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOe1 
                 249 
                 ACAUGGACAACUGCUAUAA 
               
               
                   
                 250 
                 UUAUAGCAGUUGUCCAUGUGG 
               
               
                   
               
               
                 siXOe2 
                 251 
                 CCACAUGGACAACUGCUAUAA 
               
               
                   
                 252 
                 UUAUAGCAGUUGUCCAUGUGGAA 
               
               
                   
               
               
                 siXOe1- 
                 253 
                 AmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M1 
                 254 
                 UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
               
               
                 siXOe1- 
                 255 
                 AmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2 
                 256 
                 UmUfAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
               
               
                 siXOe1- 
                 257 
                 AmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3 
                 258 
                 UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
               
               
                 siXOe2- 
                 259 
                 CmCmAmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M1 
                   
                 m 
               
               
                   
                 260 
                 UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
                   
                 AmAm 
               
               
                   
               
               
                 siXOe2- 
                 261 
                 CmCmAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2 
                 262 
                 UmUfAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmGmA 
               
               
                   
                   
                 mAm 
               
               
                   
               
               
                 siXOe2- 
                 263 
                 CmCmAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3 
                 264 
                 UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
                   
                 AmAm 
               
               
                   
               
               
                 siXOe1- 
                 265 
                 AmsCmsAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M1S 
                 266 
                 UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOe1- 
                 267 
                 AmsCmsAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2S 
                 268 
                 UmsUfsAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmsGmsG 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOe1- 
                 269 
                 AmsCmsAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3S 
                 270 
                 UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOe2- 
                 271 
                 CmsCmsAmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAm 
               
               
                 M1S 
                   
                 Am 
               
               
                   
                 272 
                 UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmG 
               
               
                   
                   
                 msAmsAm 
               
               
                   
               
               
                 siXOe2- 
                 273 
                 CmsCmsAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 274 
                 UmsUfsAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
                   
                 sAmsAm 
               
               
                   
               
               
                 siXOe2- 
                 275 
                 CmsCmsAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 276 
                 UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGmG 
               
               
                   
                   
                 msAmsAm 
               
               
                   
               
               
                 siXOe1- 
                 277 
                 AmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M1P1 
                 278 
                 P1UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGm 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOe1- 
                 279 
                 AmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2P1 
                 280 
                 P1UmUfAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
               
               
                 siXOe1- 
                 281 
                 AmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3P1 
                 282 
                 P1UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGm 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOe2- 
                 283 
                 CmCmAmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 284 
                 P1UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGm 
               
               
                   
                   
                 GmAmAm 
               
               
                   
               
               
                 siXOe2- 
                 285 
                 CmCmAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2P1 
                 286 
                 P1UmUfAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmGm 
               
               
                   
                   
                 AmAm 
               
               
                   
               
               
                 siXOe2- 
                 287 
                 CmCmAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3P1 
                 288 
                 P1UmUfAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmGm 
               
               
                   
                   
                 GmAmAm 
               
               
                   
               
               
                 siXOe1- 
                 289 
                 AmsCmsAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M1SP1 
                 290 
                 P1UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmsG 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOe1- 
                 291 
                 AmsCmsAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M2SP1 
                 292 
                 P1UmsUfsAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOe1- 
                 293 
                 AmsCmsAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmAm 
               
               
                 M3SP1 
                 294 
                 P1UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmsG 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOe2- 
                 295 
                 CmsCmsAmCmAmUmGmGmAfCfAfAmCmUmGmCmUmAmUmAm 
               
               
                 M1SP1 
                   
                 Am 
               
               
                   
                 296 
                 P1UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmG 
               
               
                   
                   
                 mGmsAmsAm 
               
               
                   
               
               
                 siXOe2- 
                 297 
                 CmsCmsAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 298 
                 P1UmsUfsAmUmAmGfCmAfGfUmUmGmUmCfCmAfUmGmUmGmG 
               
               
                   
                   
                 msAmsAm 
               
               
                   
               
               
                 siXOe2- 
                 299 
                 CmsCmsAmCmAmUmGfGmAfCfAfAmCmUmGmCmUmAmUmAmA 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 300 
                 P1UmsUfsAmUmAmGfCmAmGmUmUmGmUmCfCmAfUmGmUmG 
               
               
                   
                   
                 mGmsAmsAm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1f 
               
             
            
               
                   
               
               
                 The sixth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOf1 
                 309 
                 UAGCAAGCUCUCAGUAUCA 
               
               
                   
                 310 
                 UGAUACUGAGAGCUUGCUAGG 
               
               
                   
               
               
                 siXOf2 
                 311 
                 CCUAGCAAGCUCUCAGUAUCA 
               
               
                   
                 312 
                 UGAUACUGAGAGCUUGCUAGGCA 
               
               
                   
               
               
                 siXOf1- 
                 313 
                 UmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1 
                 314 
                 UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
               
               
                 siXOf1- 
                 315 
                 UmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2 
                 316 
                 UmGfAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
               
               
                 siXOf1- 
                 317 
                 UmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3 
                 318 
                 UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
               
               
                 siXOf2- 
                 319 
                 CmCmUmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1 
                 320 
                 UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOf2- 
                 321 
                 CmCmUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2 
                 322 
                 UmGfAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmGmC 
               
               
                   
                   
                 mAm 
               
               
                   
               
               
                 siXOf2- 
                 323 
                 CmCmUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3 
                 324 
                 UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOf1- 
                 325 
                 UmsAmsGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1S 
                 326 
                 UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOf1- 
                 327 
                 UmsAmsGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2S 
                 328 
                 UmsGfsAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmsGmsG 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOf1- 
                 329 
                 UmsAmsGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3S 
                 330 
                 UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOf2- 
                 331 
                 CmsCmsUmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M1S 
                   
                 m 
               
               
                   
                 332 
                 UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmG 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOf2- 
                 333 
                 CmsCmsUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 334 
                 UmsGfsAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
                   
                 sCmsAm 
               
               
                   
               
               
                 siXOf2- 
                 335 
                 CmsCmsUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M35 
                   
                 m 
               
               
                   
                 336 
                 UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGmG 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOf1- 
                 337 
                 UmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1P1 
                 338 
                 P1UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGm 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOf1- 
                 339 
                 UmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2P1 
                 340 
                 P1UmGfAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
               
               
                 siXOf1- 
                 341 
                 UmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3P1 
                 342 
                 P1UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGm 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOf2- 
                 343 
                 CmCmUmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1P1 
                 344 
                 P1UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGm 
               
               
                   
                   
                 GmCmAm 
               
               
                   
               
               
                 siXOf2- 
                 345 
                 CmCmUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2P1 
                 346 
                 P1UmGfAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmGm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOf2- 
                 347 
                 CmCmUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3P1 
                 348 
                 P1UmGfAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmGm 
               
               
                   
                   
                 GmCmAm 
               
               
                   
               
               
                 siXOf1- 
                 349 
                 UmsAmsGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M1SP1 
                 350 
                 P1UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmsG 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOf1- 
                 351 
                 UmsAmsGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M2SP1 
                 352 
                 P1UmsGfsAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmsGms 
               
               
                   
                   
                 Gm 
               
               
                   
               
               
                 siXOf1- 
                 353 
                 UmsAmsGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmAm 
               
               
                 M3SP1 
                 354 
                 P1UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmsG 
               
               
                   
                   
                 msGm 
               
               
                   
               
               
                 siXOf2- 
                 355 
                 CmsCmsUmAmGmCmAmAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M1SP1 
                   
                 m 
               
               
                   
                 356 
                 P1UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmG 
               
               
                   
                   
                 mGmsCmsAm 
               
               
                   
               
               
                 siXOf2- 
                 357 
                 CmsCmsUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 358 
                 P1UmsGfsAmUmAmCfUmGfAfGmAmGmCmUfUmGfCmUmAmGmG 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOf2- 
                 359 
                 CmsCmsUmAmGmCmAfAmGfCfUfCmUmCmAmGmUmAmUmCmA 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 360 
                 P1UmsGfsAmUmAmCfUmGmAmGmAmGmCmUfUmGfCmUmAmG 
               
               
                   
                   
                 mGmsCmsAm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1g 
               
             
            
               
                   
               
               
                 The seventh siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOg1 
                 369 
                 AUAAGGUUACUUGUGUUGG 
               
               
                   
                 370 
                 CCAACACAAGUAACCUUAUCC 
               
               
                   
               
               
                 siXOg2 
                 371 
                 GGAUAAGGUUACUUGUGUUGG 
               
               
                   
                 372 
                 CCAACACAAGUAACCUUAUCCUU 
               
               
                   
               
               
                 siXOg1- 
                 373 
                 AmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M1 
                 374 
                 CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
               
               
                 siXOg1- 
                 375 
                 AmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2 
                 376 
                 CmCfAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
               
               
                 siXOg1- 
                 377 
                 AmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3 
                 378 
                 CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
               
               
                 siXOg2- 
                 379 
                 GmGmAmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M1 
                   
                 m 
               
               
                   
                 380 
                 CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
                   
                 UmUm 
               
               
                   
               
               
                 siXOg2- 
                 381 
                 GmGmAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2 
                 382 
                 CmCfAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmCmU 
               
               
                   
                   
                 mUm 
               
               
                   
               
               
                 siXOg2- 
                 383 
                 GmGmAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3 
                 384 
                 CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
                   
                 UmUm 
               
               
                   
               
               
                 siXOg1- 
                 385 
                 AmsUmsAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M1S 
                 386 
                 CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOg1- 
                 387 
                 AmsUmsAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2S 
                 388 
                 CmsCfsAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmsCmsC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOg1- 
                 389 
                 AmsUmsAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3S 
                 390 
                 CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOg2- 
                 391 
                 GmsGmsAmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGm 
               
               
                 M1S 
                   
                 Gm 
               
               
                   
                 392 
                 CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 msUmsUm 
               
               
                   
               
               
                 siXOg2- 
                 393 
                 GmsGmsAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 394 
                 CmsCfsAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmCms 
               
               
                   
                   
                 UmsUm 
               
               
                   
               
               
                 siXOg2- 
                 395 
                 GmsGmsAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 396 
                 CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 msUmsUm 
               
               
                   
               
               
                 siXOg1- 
                 397 
                 AmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M1P1 
                 398 
                 P1CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOg1- 
                 399 
                 AmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2P1 
                 400 
                 P1CmCfAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
               
               
                 siXOg1- 
                 401 
                 AmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3P1 
                 402 
                 P1CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOg2- 
                 403 
                 GmGmAmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 404 
                 P1CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 mUmUm 
               
               
                   
               
               
                 siXOg2- 
                 405 
                 GmGmAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2P1 
                 406 
                 P1CmCfAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmCm 
               
               
                   
                   
                 UmUm 
               
               
                   
               
               
                 siXOg2- 
                 407 
                 GmGmAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3P1 
                 408 
                 P1CmCfAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 mUmUm 
               
               
                   
               
               
                 siXOg1- 
                 409 
                 AmsUmsAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M1SP1 
                 410 
                 P1CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmsC 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOg1- 
                 411 
                 AmsUmsAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M2SP1 
                 412 
                 P1CmsCfsAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOg1- 
                 413 
                 AmsUmsAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmGm 
               
               
                 M3SP1 
                 414 
                 P1CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmsC 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOg2- 
                 415 
                 GmsGmsAmUmAmAmGmGmUfUfAfCmUmUmGmUmGmUmUmGm 
               
               
                 M1SP1 
                   
                 Gm 
               
               
                   
                 416 
                 P1CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCm 
               
               
                   
                   
                 CmsUmsUm 
               
               
                   
               
               
                 siXOg2- 
                 417 
                 GmsGmsAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 418 
                 P1CmsCfsAmAmCmAfCmAfAfGmUmAmAmCfCmUfUmAmUmCmC 
               
               
                   
                   
                 msUmsUm 
               
               
                   
               
               
                 siXOg2- 
                 419 
                 GmsGmsAmUmAmAmGfGmUfUfAfCmUmUmGmUmGmUmUmGmG 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 420 
                 P1CmsCfsAmAmCmAfCmAmAmGmUmAmAmCfCmUfUmAmUmCm 
               
               
                   
                   
                 CmsUmsUm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1h 
               
             
            
               
                   
               
               
                 The eighth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOh1 
                 429 
                 GAAAAUCACCUAUGAAGAA 
               
               
                   
                 430 
                 UUCUUCAUAGGUGAUUUUCAC 
               
               
                   
               
               
                 siXOh2 
                 431 
                 GUGAAAAUCACCUAUGAAGAA 
               
               
                   
                 432 
                 UUCUUCAUAGGUGAUUUUCACCC 
               
               
                   
               
               
                 siXOh1- 
                 433 
                 GmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M1 
                 434 
                 UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
               
               
                 siXOh1- 
                 435 
                 GmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2 
                 436 
                 UmUfCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
               
               
                 siXOh1- 
                 437 
                 GmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3 
                 438 
                 UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
               
               
                 siXOh2- 
                 439 
                 GmUmGmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M1 
                   
                 m 
               
               
                   
                 440 
                 UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
                   
                 CmCm 
               
               
                   
               
               
                 siXOh2- 
                 441 
                 GmUmGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2 
                 442 
                 UmUfCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmCmC 
               
               
                   
                   
                 mCm 
               
               
                   
               
               
                 siXOh2- 
                 443 
                 GmUmGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3 
                 444 
                 UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
                   
                 CmCm 
               
               
                   
               
               
                 siXOh1- 
                 445 
                 GmsAmsAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M1S 
                 446 
                 UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmsAms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOh1- 
                 447 
                 GmsAmsAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2S 
                 448 
                 UmsUfsCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmsAmsC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOh1- 
                 449 
                 GmsAmsAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3S 
                 450 
                 UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmsAms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOh2- 
                 451 
                 GmsUmsGmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAm 
               
               
                 M1S 
                   
                 Am 
               
               
                   
                 452 
                 UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 msCmsCm 
               
               
                   
               
               
                 siXOh2- 
                 453 
                 GmsUmsGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 454 
                 UmsUfsCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmCms 
               
               
                   
                   
                 CmsCm 
               
               
                   
               
               
                 siXOh2- 
                 455 
                 GmsUmsGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 456 
                 UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 msCmsCm 
               
               
                   
               
               
                 siXOh1- 
                 457 
                 GmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M1P1 
                 458 
                 P1UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOh1- 
                 459 
                 GmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2P1 
                 460 
                 P1UmUfCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
               
               
                 siXOh1- 
                 461 
                 GmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3P1 
                 462 
                 P1UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOh2- 
                 463 
                 GmUmGmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 464 
                 P1UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 mCmCm 
               
               
                   
               
               
                 siXOh2- 
                 465 
                 GmUmGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2P1 
                 466 
                 P1UmUfCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmCm 
               
               
                   
                   
                 CmCm 
               
               
                   
               
               
                 siXOh2- 
                 467 
                 GmUmGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3P1 
                 468 
                 P1UmUfCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 mCmCm 
               
               
                   
               
               
                 siXOh1- 
                 469 
                 GmsAmsAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M1SP1 
                 470 
                 P1UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmsA 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOh1- 
                 471 
                 GmsAmsAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M2SP1 
                 472 
                 P1UmsUfsCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmsAms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOh1- 
                 473 
                 GmsAmsAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmAm 
               
               
                 M3SP1 
                 474 
                 P1UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmsA 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOh2- 
                 475 
                 GmsUmsGmAmAmAmAmUmCfAfCfCmUmAmUmGmAmAmGmAm 
               
               
                 M1SP1 
                   
                 Am 
               
               
                   
                 476 
                 P1UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmA 
               
               
                   
                   
                 mCmsCmsCm 
               
               
                   
               
               
                 siXOh2- 
                 477 
                 GmsUmsGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 478 
                 P1UmsUfsCmUmUmCfAmUfAfGmGmUmGmAfUmUfUmUmCmAmC 
               
               
                   
                   
                 msCmsCm 
               
               
                   
               
               
                 siXOh2- 
                 479 
                 GmsUmsGmAmAmAmAfUmCfAfCfCmUmAmUmGmAmAmGmAmA 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 480 
                 P1UmsUfsCmUmUmCfAmUmAmGmGmUmGmAfUmUfUmUmCmA 
               
               
                   
                   
                 mCmsCmsCm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1i 
               
             
            
               
                   
               
               
                 The ninth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOi1 
                 489 
                 GAUGCUAUAAAGAACAACU 
               
               
                   
                 490 
                 AGUUGUUCUUUAUAGCAUCCU 
               
               
                   
               
               
                 siXOi2 
                 491 
                 AGGAUGCUAUAAAGAACAACU 
               
               
                   
                 492 
                 AGUUGUUCUUUAUAGCAUCCUCA 
               
               
                   
               
               
                 siXOi1- 
                 493 
                 GmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M1 
                 494 
                 AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
               
               
                 siXOi1- 
                 495 
                 GmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2 
                 496 
                 AmGfUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
               
               
                 siXOi1- 
                 497 
                 GmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3 
                 498 
                 AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
               
               
                 siXOi2- 
                 499 
                 AmGmGmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                 500 
                 AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOi2- 
                 501 
                 AmGmGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2 
                 502 
                 AmGfUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmUmC 
               
               
                   
                   
                 mAm 
               
               
                   
               
               
                 siXOi2- 
                 503 
                 AmGmGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3 
                 504 
                 AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOi1- 
                 505 
                 GmsAmsUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M1S 
                 506 
                 AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmsCms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOi1- 
                 507 
                 GmsAmsUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2S 
                 508 
                 AmsGfsUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmsCmsU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOi1- 
                 509 
                 GmsAmsUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3S 
                 510 
                 AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmsCms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOi2- 
                 511 
                 AmsGmsGmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                 512 
                 AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOi2- 
                 513 
                 AmsGmsGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 514 
                 AmsGfsUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmUms 
               
               
                   
                   
                 CmsAm 
               
               
                   
               
               
                 siXOi2- 
                 515 
                 AmsGmsGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 516 
                 AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOi1- 
                 517 
                 GmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M1P1 
                 518 
                 P1AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOi1- 
                 519 
                 GmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2P1 
                 520 
                 P1AmGfUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
               
               
                 siXOi1- 
                 521 
                 GmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3P1 
                 522 
                 P1AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOi2- 
                 523 
                 AmGmGmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 524 
                 P1AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 mCmAm 
               
               
                   
               
               
                 siXOi2- 
                 525 
                 AmGmGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2P1 
                 526 
                 P1AmGfUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmUm 
               
               
                   
                   
                 CmAm 
               
               
                   
               
               
                 siXOi2- 
                 527 
                 AmGmGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3P1 
                 528 
                 P1AmGfUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 mCmAm 
               
               
                   
               
               
                 siXOi1- 
                 529 
                 GmsAmsUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M1SP1 
                 530 
                 P1AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmsC 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOi1- 
                 531 
                 GmsAmsUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M2SP1 
                 532 
                 P1AmsGfsUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmsCms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOi1- 
                 533 
                 GmsAmsUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmUm 
               
               
                 M3SP1 
                 534 
                 P1AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmsC 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOi2- 
                 535 
                 AmsGmsGmAmUmGmCmUmAfUfAfAmAmGmAmAmCmAmAmCm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 536 
                 P1AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmC 
               
               
                   
                   
                 mUmsCmsAm 
               
               
                   
               
               
                 siXOi2- 
                 537 
                 AmsGmsGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 538 
                 P1AmsGfsUmUmGmUfUmCfUfUmUmAmUmAfGmCfAmUmCmCmU 
               
               
                   
                   
                 msCmsAm 
               
               
                   
               
               
                 siXOi2- 
                 539 
                 AmsGmsGmAmUmGmCfUmAfUfAfAmAmGmAmAmCmAmAmCmU 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 540 
                 P1AmsGfsUmUmGmUfUmCmUmUmUmAmUmAfGmCfAmUmCmC 
               
               
                   
                   
                 mUmsCmsAm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1j 
               
             
            
               
                   
               
               
                 The tenth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOj1 
                 549 
                 GAACAACUCCUUUUAUGGA 
               
               
                   
                 550 
                 UCCAUAAAAGGAGUUGUUCUU 
               
               
                   
               
               
                 siXOj2 
                 551 
                 AAGAACAACUCCUUUUAUGGA 
               
               
                   
                 552 
                 UCCAUAAAAGGAGUUGUUCUUUA 
               
               
                   
               
               
                 siXOj1-M 
                 553 
                 GmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 1 
                 554 
                 UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
               
               
                 siXOj1-M 
                 555 
                 GmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 2 
                 556 
                 UmCfCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
               
               
                 siXOj1-M 
                 557 
                 GmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 3 
                 558 
                 UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
               
               
                 siXOj2-M 
                 559 
                 AmAmGmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 1 
                   
                 m 
               
               
                   
                 560 
                 UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
                   
                 UmAm 
               
               
                   
               
               
                 siXOj2-M 
                 561 
                 AmAmGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 2 
                 562 
                 UmCfCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmUmU 
               
               
                   
                   
                 mAm 
               
               
                   
               
               
                 siXOj2-M 
                 563 
                 AmAmGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 3 
                 564 
                 UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
                   
                 UmAm 
               
               
                   
               
               
                 siXOj1-M 
                 565 
                 GmsAmsAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 1S 
                 566 
                 UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOj1-M 
                 567 
                 GmsAmsAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 2S 
                 568 
                 UmsCfsCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmsUmsU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOj1-M 
                 569 
                 GmsAmsAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 3S 
                 570 
                 UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOj2-M 
                 571 
                 AmsAmsGmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGm 
               
               
                 1S 
                   
                 Am 
               
               
                   
                 572 
                 UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmU 
               
               
                   
                   
                 msUmsAm 
               
               
                   
               
               
                 siXOj2-M 
                 573 
                 AmsAmsGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 2S 
                   
                 m 
               
               
                   
                 574 
                 UmsCfsCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
                   
                 sUmsAm 
               
               
                   
               
               
                 siXOj2-M 
                 575 
                 AmsAmsGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 3S 
                   
                 m 
               
               
                   
                 576 
                 UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUmU 
               
               
                   
                   
                 msUmsAm 
               
               
                   
               
               
                 siXOj1- 
                 577 
                 GmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M1P1 
                 578 
                 P1UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOj1- 
                 579 
                 GmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M2P1 
                 580 
                 P1UmCfCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
               
               
                 siXOj1- 
                 581 
                 GmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M3P1 
                 582 
                 P1UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOj2- 
                 583 
                 AmAmGmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 584 
                 P1UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUm 
               
               
                   
                   
                 UmUmAm 
               
               
                   
               
               
                 siXOj2- 
                 585 
                 AmAmGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M2P1 
                 586 
                 P1UmCfCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmUm 
               
               
                   
                   
                 UmAm 
               
               
                   
               
               
                 siXOj2- 
                 587 
                 AmAmGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M3P1 
                 588 
                 P1UmCfCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmUm 
               
               
                   
                   
                 UmUmAm 
               
               
                   
               
               
                 siXOj1- 
                 589 
                 GmsAmsAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M1SP1 
                 590 
                 P1UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmsU 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOj1- 
                 591 
                 GmsAmsAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M2SP1 
                 592 
                 P1UmsCfsCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmsUms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOj1- 
                 593 
                 GmsAmsAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmAm 
               
               
                 M3SP1 
                 594 
                 P1UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmsU 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOj2- 
                 595 
                 AmsAmsGmAmAmCmAmAmCfUfCfCmUmUmUmUmAmUmGmGm 
               
               
                 M1SP1 
                   
                 Am 
               
               
                   
                 596 
                 P1UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmU 
               
               
                   
                   
                 mUmsUmsAm 
               
               
                   
               
               
                 siXOj2- 
                 597 
                 AmsAmsGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 598 
                 P1UmsCfsCmAmUmAfAmAfAfGmGmAmGmUfUmGfUmUmCmUmU 
               
               
                   
                   
                 msUmsAm 
               
               
                   
               
               
                 siXOj2- 
                 599 
                 AmsAmsGmAmAmCmAfAmCfUfCfCmUmUmUmUmAmUmGmGmA 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 600 
                 P1UmsCfsCmAmUmAfAmAmAmGmGmAmGmUfUmGfUmUmCmU 
               
               
                   
                   
                 mUmsUmsAm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1k 
               
             
            
               
                   
               
               
                 The eleventh siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOk1 
                 609 
                 CUUGCUCUGAAGUAGAAAU 
               
               
                   
                 610 
                 AUUUCUACUUCAGAGCAAGCC 
               
               
                   
               
               
                 siXOk2 
                 611 
                 GGCUUGCUCUGAAGUAGAAAU 
               
               
                   
                 612 
                 AUUUCUACUUCAGAGCAAGCCAC 
               
               
                   
               
               
                 siXOk1- 
                 613 
                 CmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M1 
                 614 
                 AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
               
               
                 siXOk1- 
                 615 
                 CmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2 
                 616 
                 AmUfUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
               
               
                 siXOk1- 
                 617 
                 CmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3 
                 618 
                 AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
               
               
                 siXOk2- 
                 619 
                 GmGmCmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                 620 
                 AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOk2- 
                 621 
                 GmGmCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2 
                 622 
                 AmUfUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmCmA 
               
               
                   
                   
                 mCm 
               
               
                   
               
               
                 siXOk2- 
                 623 
                 GmGmCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3 
                 624 
                 AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOk1- 
                 625 
                 CmsUmsUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M1S 
                 626 
                 AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOk1- 
                 627 
                 CmsUmsUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2S 
                 628 
                 AmsUfsUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmsCmsC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOk1- 
                 629 
                 CmsUmsUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3S 
                 630 
                 AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOk2- 
                 631 
                 GmsGmsCmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                 632 
                 AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOk2- 
                 633 
                 GmsGmsCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 634 
                 AmsUfsUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmCms 
               
               
                   
                   
                 AmsCm 
               
               
                   
               
               
                 siXOk2- 
                 635 
                 GmsGmsCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 636 
                 AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOk1- 
                 637 
                 CmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M1P1 
                 638 
                 P1AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOk1- 
                 639 
                 CmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2P1 
                 640 
                 P1AmUfUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
               
               
                 siXOk1- 
                 641 
                 CmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3P1 
                 642 
                 P1AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOk2- 
                 643 
                 GmGmCmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 644 
                 P1AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 mAmCm 
               
               
                   
               
               
                 siXOk2- 
                 645 
                 GmGmCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2P1 
                 646 
                 P1AmUfUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmCm 
               
               
                   
                   
                 AmCm 
               
               
                   
               
               
                 siXOk2- 
                 647 
                 GmGmCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3P1 
                 648 
                 P1AmUfUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 mAmCm 
               
               
                   
               
               
                 siXOk1- 
                 649 
                 CmsUmsUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M1SP1 
                 650 
                 P1AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmsC 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOk1- 
                 651 
                 CmsUmsUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M2SP1 
                 652 
                 P1AmsUfsUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmsCms 
               
               
                   
                   
                 Cm 
               
               
                   
               
               
                 siXOk1 
                 653 
                 CmsUmsUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmUm 
               
               
                 M3SP1 
                 654 
                 P1AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmsC 
               
               
                   
                   
                 msCm 
               
               
                   
               
               
                 siXOk2- 
                 655 
                 GmsGmsCmUmUmGmCmUmCfUfGfAmAmGmUmAmGmAmAmAm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 656 
                 P1AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCm 
               
               
                   
                   
                 CmsAmsCm 
               
               
                   
               
               
                 siXOk2- 
                 657 
                 GmsGmsCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 658 
                 P1AmsUfsUmUmCmUfAmCfUfUmCmAmGmAfGmCfAmAmGmCmC 
               
               
                   
                   
                 msAmsCm 
               
               
                   
               
               
                 siXOk2- 
                 659 
                 GmsGmsCmUmUmGmCfUmCfUfGfAmAmGmUmAmGmAmAmAmU 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 660 
                 P1AmsUfsUmUmCmUfAmCmUmUmCmAmGmAfGmCfAmAmGmCm 
               
               
                   
                   
                 CmsAmsCm 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1l 
               
             
            
               
                   
               
               
                 The twelveth siRNA sequence of the present disclosure 
               
            
           
           
               
               
               
            
               
                 siRNA 
                 SEQ 
                   
               
               
                 No. 
                 ID NO: 
                 Sequence direction 5′-3′ 
               
               
                   
               
               
                 siXOl1 
                 669 
                 CUUCUUUGCCAUCAAAGAU 
               
               
                   
                 670 
                 AUCUUUGAUGGCAAAGAAGAU 
               
               
                   
               
               
                 siXOl2 
                 671 
                 AUCUUCUUUGCCAUCAAAGAU 
               
               
                   
                 672 
                 AUCUUUGAUGGCAAAGAAGAUAG 
               
               
                   
               
               
                 siXOl1- 
                 673 
                 CmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M1 
                 674 
                 AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
               
               
                 siXOl1- 
                 675 
                 CmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2 
                 676 
                 AmUfCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
               
               
                 siXOl1- 
                 677 
                 CmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3 
                 678 
                 AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
               
               
                 siXOl2- 
                 679 
                 AmUmCmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M1 
                   
                 m 
               
               
                   
                 680 
                 AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
                   
                 AmGm 
               
               
                   
               
               
                 siXOl2- 
                 681 
                 AmUmCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2 
                 682 
                 AmUfCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmUmA 
               
               
                   
                   
                 mGm 
               
               
                   
               
               
                 siXOl2- 
                 683 
                 AmUmCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3 
                 684 
                 AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
                   
                 AmGm 
               
               
                   
               
               
                 siXOl1- 
                 685 
                 CmsUmsUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M1S 
                 686 
                 AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmsAms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOl1- 
                 687 
                 CmsUmsUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2S 
                 688 
                 AmsUfsCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmsAmsU 
               
               
                   
                   
                 m 
               
               
                   
               
               
                 siXOl1- 
                 689 
                 CmsUmsUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3S 
                 690 
                 AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmsAms 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOl2- 
                 691 
                 AmsUmsCmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAm 
               
               
                 M1S 
                   
                 Um 
               
               
                   
                 692 
                 AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmU 
               
               
                   
                   
                 msAmsGm 
               
               
                   
               
               
                 siXOl2- 
                 693 
                 AmsUmsCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M2S 
                   
                 m 
               
               
                   
                 694 
                 AmsUfsCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
                   
                 sAmsGm 
               
               
                   
               
               
                 siXOl2- 
                 695 
                 AmsUmsCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M3S 
                   
                 m 
               
               
                   
                 696 
                 AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAmU 
               
               
                   
                   
                 msAmsGm 
               
               
                   
               
               
                 siXOl1- 
                 697 
                 CmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M1P1 
                 698 
                 P1AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOl1- 
                 699 
                 CmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2P1 
                 700 
                 P1AmUfCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
               
               
                 siXOl1- 
                 701 
                 CmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3P1 
                 702 
                 P1AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAm 
               
               
                   
                   
                 Um 
               
               
                   
               
               
                 siXOl2- 
                 703 
                 AmUmCmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M1P1 
                   
                 m 
               
               
                   
                 704 
                 P1AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAm 
               
               
                   
                   
                 UmAmGm 
               
               
                   
               
               
                 siXOl2- 
                 705 
                 AmUmCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2P1 
                 706 
                 P1AmUfCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmUm 
               
               
                   
                   
                 AmGm 
               
               
                   
               
               
                 siXOl2- 
                 707 
                 AmUmCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3P1 
                 708 
                 P1AmUfCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmAm 
               
               
                   
                   
                 UmAmGm 
               
               
                   
               
               
                 siXOl1- 
                 709 
                 CmsUmsUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M1SP1 
                 710 
                 P1AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmsA 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOl1- 
                 711 
                 CmsUmsUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M2SP1 
                 712 
                 P1AmsUfsCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmsAm 
               
               
                   
                   
                 sUm 
               
               
                   
               
               
                 siXOl1- 
                 713 
                 CmsUmsUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmUm 
               
               
                 M3SP1 
                 714 
                 P1AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmsA 
               
               
                   
                   
                 msUm 
               
               
                   
               
               
                 siXOl2- 
                 715 
                 AmsUmsCmUmUmCmUmUmUfGfCfCmAmUmCmAmAmAmGmAm 
               
               
                 M1SP1 
                   
                 Um 
               
               
                   
                 716 
                 P1AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmA 
               
               
                   
                   
                 mUmsAmsGm 
               
               
                   
               
               
                 siXOl2- 
                 717 
                 AmsUmsCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M2SP1 
                   
                 m 
               
               
                   
                 718 
                 P1AmsUfsCmUmUmUfGmAfUfGmGmCmAmAfAmGfAmAmGmAmU 
               
               
                   
                   
                 msAmsGm 
               
               
                   
               
               
                 siXOl2- 
                 719 
                 AmsUmsCmUmUmCmUfUmUfGfCfCmAmUmCmAmAmAmGmAmU 
               
               
                 M3SP1 
                   
                 m 
               
               
                   
                 720 
                 P1AmsUfsCmUmUmUfGmAmUmGmGmCmAmAfAmGfAmAmGmA 
               
               
                   
                   
                 mUmsAmsGm 
               
               
                   
               
            
           
         
       
     
     wherein, capital letters C, G, U, and A indicate the base composition of the nucleotides; the lowercase m indicates that the nucleotide adjacent to the left side of the letter m is a methoxy modified nucleotide; the lowercase f indicates that the nucleotide adjacent to the left side of the letter f is a fluoro modified nucleotide; the lowercase letter s indicates that the two nucleotides adjacent to the left and right of the letter s are linked by phosphorothioate; and P1 represents that the nucleotide adjacent to the right side of P1 is a 5′-phosphate nucleotide or a 5′-phosphate analogue modified nucleotide. In some embodiments, P1 represents specifically modified VP, Ps or P, wherein the letter combination VP represents that the nucleotide adjacent to the right side of the letter combination VP is a 5′-(E)-vinylphosphonate (E-VP) modified nucleotide, the letter combination Ps represents that the nucleotide adjacent to the right side of the letter combination Ps is a phosphorothioate modified nucleotide, and the capital letter P represents that the nucleotide adjacent to the right side of the letter P is a 5′-phosphate nucleotide. 
     In the siRNA or the siRNA conjugate of the present disclosure, each pair of adjacent nucleotides is linked via a phosphodiester bond or phosphorothioate diester bond. The non-bridging oxygen atom or sulfur atom in the phosphodiester bond or phosphorothioate diester bond is negatively charged, and may be present in the form of hydroxy or sulfhydryl. Moreover, the hydrogen ion in the hydroxy or sulfhydryl may be partially or completely substituted with a cation. The cation may be any cation, such as a metal cation, an ammonium ion NH4 +  or an organic ammonium cation. In order to increase solubility, in some embodiments, the cation is selected from one or more of an alkali metal ion, an ammonium cation formed by a tertiary amine and a quaternary ammonium cation. The alkali metal ion may be K +  and/or Na + , and the cation formed by the tertiary amine may be an ammonium ion formed by triethylamine and/or an ammonium ion formed by N,N-diisopropylethylamine. Thus, the siRNA or siRNA conjugate of the present disclosure may be at least partially present in the form of salt. In one embodiment, the non-bridging oxygen atom or sulfur atom in the phosphodiester bond or phosphorothioate diester bond at least partly binds to a sodium ion, and thus the siRNA or the siRNA conjugate of the present disclosure is present or partially present in the form of sodium salt. 
     Those skilled in the art clearly know that a modified nucleotide group may be introduced into the siRNA of the present disclosure by a nucleoside monomer having a corresponding modification. The methods for preparing the nucleoside monomer having the corresponding modification and the methods for introducing the modified nucleotide group into the siRNA are also well-known to those skilled in the art. All the modified nucleoside monomers may be either commercially available or prepared by known methods. 
     Preparation of the siRNA Conjugate as Shown by Formula (308) 
     The siRNA conjugate as shown by Formula (308) may be prepared by any appropriate synthetic routes. 
     In some embodiments, the siRNA conjugate as shown by Formula (308) may be prepared by the following method. The method comprises: successively linking nucleoside monomers in the direction from 3′ to 5′ according to the nucleotide types and sequences in the sense strand and antisense strand respectively under the condition of solid phase phosphoramidite synthesis, wherein the step of linking each nucleoside monomer comprises a four-step reaction of deprotection, coupling, capping, and oxidation or sulfurization; isolating the sense strand and the antisense strand of the siRNA; and annealing; wherein the siRNA is the siRNA of the present disclosure mentioned above. 
     Moreover, the method further comprises: contacting the compound as shown by Formula (321) with a nucleoside monomer or a nucleotide sequence linked to a solid phase support under coupling reaction condition and in the presence of a coupling agent, thereby linking the compound as shown by Formula (321) to the nucleotide sequence through a coupling reaction. Hereinafter, the compound as shown by Formula (321) is also called a conjugating molecule. 
     
       
         
         
             
             
         
       
     
     wherein: 
     R 4  is a group capable of binding to the siRNA represented by Nu in the compound as shown by Formula (308). In some embodiments, R 4  is a group capable of binding to the siRNA represented by Nu via a covalent bond. In some embodiments, R 4  is a group capable of being conjugated to any functional group of the siRNA represented by Nu via a phosphodiester bond by reaction; 
     Each S 1  is independently an M 1 , which is a group formed by substituting all active hydroxy with a YCOO— group, wherein each Y is independently selected from one of methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, ethyl, n-propyl, isopropyl, phenyl, halophenyl, and alkylphenyl. In some embodiments, Y is a methyl. 
     Definitions and options of n1, n3, m1, m2, m3, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , L 1 , and M 1  are respectively as described above. 
     R 4  is selected to achieve the linkage to the N atom on a nitrogenous backbone and to provide a suitable reaction site for synthesizing the siRNA conjugate as shown by Formula (308). In some embodiments, R 4  comprises a R 2  linking group or a protected R 2  linking group, and can form a functional group as shown by Formula (A59) with an siRNA via reaction. 
     In some embodiments, R4 comprises a first functional group that can react with a group on an siRNA or a nucleoside monomer represented by Nu to form a phosphite ester, and a second functional group that can form a covalent bond with a hydroxy or an amino, or comprises a solid phase support linked via the covalent bond. In some embodiments, the first functional group is a phosphoramidite, a hydroxy or a protected hydroxy. In some embodiments, the second functional group is a phosphoramidite, a carboxyl or a carboxylate. In some embodiments, the second functional group is a solid phase support linked to the rest of the molecule via a covalent bond which is formed by a hydroxy or an amino. In some embodiments, the solid phase support is linked via a phosphoester bond, a carboxyl ester bond, or an amide bond. In some embodiments, the solid phase support is a resin. 
     In some embodiments, the first functional group comprises a hydroxy, —OR k  or a group as shown by Formula (C3); and the second functional group comprises a group as shown by Formula (C1), (C2), (C3), (C1′), or (C3′): 
     
       
         
         
             
             
         
       
     
     wherein q 1  is an integer of 1-4, X is O or NH, M +  is a cation, R k  is a hydroxy protecting group, SPS represents a solid phase support, and   represents the site where a group is covalently linked. 
     In some embodiments, the first functional group comprises a phosphoramidite group as shown by Formula (C3). The phosphoramidite group can form a phosphite ester with a hydroxy at any position on a nucleotide such as a 2′ or 3′ hydroxy by a coupling reaction, and the phosphite ester can form a phosphodiester bond or phosphorothioate ester bond as shown by Formula (A59) via oxidation or sulfurization, so as to conjugate the conjugating molecule to the siRNA. In this case, even if the second functional group does not exist, the compound as shown by Formula (321) will still be able to be conjugated to the nucleotide, without affecting the acquisition of the siRNA conjugate as shown by Formula (308). Under such circumstances, after obtaining a sense strand or an antisense strand of the siRNA by a method such as solid phase phosphoramidite synthesis, the compound as shown by Formula (321) is reacted with a hydroxy on the terminal nucleotide of the nucleotide sequence, and phosphodiester bonding or phosphorothioate bonding is formed by a subsequent oxidation or sulfurization process, thereby conjugating the compound as shown by Formula (321) to the siRNA. 
     In some embodiments, the first functional group comprises a protected hydroxy. In some embodiments, the second functional group comprises a group that can react with a solid phase support to provide a conjugating molecule comprising the solid phase support. In some embodiments, the second functional group comprises a carboxyl, a carboxylate or a phosphoramidite as shown by Formula (C1), (C2) or (C3). When the second functional group comprises a carboxyl or a carboxylate, the compound as shown by Formula (321) reacts with a hydroxy or an amino on a solid phase support such as a resin via an esterification or an amidation reaction, to form a conjugating molecule comprising the solid phase support linked via a carboxyl ester bond. When the second functional group comprises a phosphoramidite functional group, the compound as shown by Formula (321) may be coupled with a hydroxy on a universal solid phase support, such as a resin, and form, by oxidation, a conjugating molecule comprising the solid phase support linked via a phosphodiester bond. Subsequently, starting from the above product linked to the solid phase support, the nucleoside monomers are linked sequentially by a solid phase phosphoramidite synthesis method, thereby obtaining a sense or strand or an antisense strand of the siRNA linked to the conjugation group. During the solid phase phosphoramidite synthesis, the first functional group is deprotected, and then coupled with a phosphoramidite group on a nucleoside monomer under coupling reaction condition. 
     In some embodiments, the first functional group comprises a hydroxy or a protected hydroxy; and the second functional group comprises a solid phase support linked via a carboxyl ester bond, a solid phase support linked via an amide bond or a solid phase support linked via a phosphoester bond, as shown by Formula (C1′) or (C3′). In this case, starting from the compound as shown by Formula (321) in place of the solid phase support, the nucleoside monomers are linked sequentially by a solid phase phosphoramidite synthesis, thereby obtaining a sense strand or an antisense strand of the siRNA linked to a conjugating group. 
     In some embodiments, the carboxylate may be expressed as —COO-M + , wherein M +  is a cation such as one of a metal cation, an ammonium cation NH4 +  and an organic ammonium cation. In one embodiment, the metal ion may be an alkali metal ion, such as K +  or Na + . In order to increase solubility and facilitate the reaction, in some embodiments, the organic ammonium ion is an ammonium cation formed by a tertiary amine, or a quaternary ammonium cation, such as an ammonium ion formed by triethylamine or an ammonium ion formed by N,N-diisopropylethylamine. In some embodiments, the carboxylate is a triethylamine carboxylate or an N,N-diisopropylethylamine carboxylate. 
     In some embodiments, R 4  comprises a structure as shown by Formula (B9), (B10), (B9′), (B10′), (B11), (B12), (B11′) or (B12′): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein q 1  is an integer of 1-4, q 2  is an integer of 1-10, X is O or NH, M +  is a cation, R k  is a hydroxy protecting group, SPS represents a solid phase support, and   represents a site where a group is covalently linked. In some embodiments, q 1  is 1 or 2. In some embodiments, q2 is an integer of 1-5. In some embodiments, R 4  comprises a structure as shown by Formula (B9) or (B10). In some embodiments, R 4  comprises a structure as shown by Formula (B11) or (B12). 
     In some embodiments, R k  is one or more of Tr(trityl), MMTr(4-methoxytrityl), DMTr(4,4′-dimethoxytrityl), and TMTr(4,4′,4″-trimethoxytrityl). In some embodiments, R k  may be DMTr, i.e., 4,4′-dimethoxytrityl. 
     The definition of L 1  is as described above. 
     In some embodiments, L 1  is used to link the M 1  targeting group to the N atom on the nitrogenous backbone, thereby providing liver targeting function for the siRNA conjugate as shown by Formula (308). In some embodiments, L 1  comprises any one of A1-A26, or the combination thereof. 
     According to the description above, those skilled in the art would easily understand that as compared with the well-known solid phase phosphoramidite synthesis methods in the art, an siRNA conjugate in which a conjugating molecule is linked to any possible position of the nucleotide sequence can be obtained through the above first functional group and an optional second functional group. For example, the conjugating molecule is linked to a terminal of the nucleotide sequence or to either terminal of the nucleotide sequence. Correspondingly, unless otherwise specified, in the following description regarding siRNA conjugate and/or conjugating molecule preparation, when referring to the reactions such as “deprotection”, “coupling”, “capping”, “oxidation”, “sulfurization”, it will be understood that the reaction conditions and agents involved in the well-known phosphoramidite nucleic acid solid phase synthesis methods in the art would also apply to these reactions. Exemplary reaction conditions and agents will be described in detail hereinafter. 
     In some embodiments, each S 1  is independently an M 1 . In some embodiments, each S 1  is independently a group formed by protecting at least one active hydroxy in M 1  with a hydroxy protecting group. In some embodiments, each S 1  is independently a group formed by protecting all active hydroxys in Mi with hydroxy protecting groups. In some embodiments, any hydroxy protecting group known to those skilled in the art may be used to protect the active hydroxy in M 1 . In some embodiments, the protected hydroxy is expressed as the formula YCOO—, wherein each Y is independently selected from the group consisting of C 1 -C 10  alkyl and C 6 -C 10  aryl, wherein the C 1 -C 10  alkyl and C 6 -C 10  aryl are optionally substituted with one or more substituents selected from the group consisting of halo and C 1 -C 6  alkyl. In some embodiments, each Y is independently selected from the group consisting of methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, ethyl, n-propyl, isopropyl, phenyl, halophenyl, and C 1 -C 6  alkylphenyl. 
     In some embodiments, each S 1  is independently selected from the group consisting of Formulae A46-A54: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, S 1  is Formula A49 or A50. 
     In some embodiments, each Y is independently selected from one of methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, ethyl, n-propyl, isopropyl, phenyl, halophenyl, and alkylphenyl. In some embodiments, Y is a methyl. 
     As mentioned previously, the method for preparing the siRNA conjugate as shown by Formula (308) further comprises the following steps of: synthesizing the other strand of the siRNA (for example, when the sense strand of the siRNA linked to the conjugating molecule is synthesized in the above step, the method further comprises synthesizing the antisense strand of the siRNA by the solid phase synthesis method, and vice versa); isolating the sense strand and the antisense strand; and annealing. In particular, in the isolating step, the solid phase support linked to the nucleotide sequence and/or the conjugating molecule is cleaved and at the same time the necessary protecting group is removed (in this case, each S 1  group in the compound as shown by Formula (321) is converted to a corresponding M 1  targeting group), thereby providing the sense strand (or antisense strand) of the siRNA linked to the conjugating molecule and the corresponding antisense strand (or sense strand). The sense strand and the antisense strand are annealed to form a double-stranded RNA structure, thereby obtaining the siRNA conjugate as shown by Formula (308). 
     In some embodiments, the method for preparing the siRNA conjugate as shown by Formula (308) further comprises the following steps of: contacting the compound as shown by Formula (321) with the first nucleoside monomer at 3′terminal of the sense strand or antisense strand under coupling reaction condition in the presence of a coupling agent, thereby linking the compound as shown by Formula (321) to the first nucleotide in the sequence; successively linking nucleoside monomers in the direction from 3′ to 5′ to synthesize the sense strand or the antisense strand of the siRNA according to the desired nucleotide type and sequence of the sense strand or antisense strand, under the condition of solid phase phosphoramidite synthesis; wherein the compound as shown by Formula (321) is a compound in which R4 comprises a first functional group and a second functional group, the first functional group comprises a protected hydroxy and the second functional group comprises a group as shown by Formula (C1′) or (C3′), and the compound as shown by Formula (321) is deprotected before linked to the first nucleoside monomer; and the linking of each nucleoside monomer comprises a four-step reaction of deprotection, coupling, capping, and oxidation or sulfurization, thus obtaining a sense strand or an antisense strand of a nucleic acid linked to the conjugating molecule; successively linking the nucleoside monomers in the direction from 3′ to 5′ to synthesize the sense strand or antisense strand of the nucleic acid according to the nucleotide type and sequence of the sense strand or the antisense strand, under the condition of solid phase phosphoramidite synthesis; wherein the linking of each nucleoside monomer comprises a four-step reaction of deprotection, coupling, capping, and oxidation or sulfurization; removing the protecting groups and cleaving the solid phase support; isolating and purifying to obtain the sense strand and the antisense strand; and annealing. 
     In some embodiments, the method for preparing the siRNA conjugate as shown by Formula (308) further comprises the following steps of: successively linking nucleoside monomers in the direction from 3′ to 5′ to synthesize the sense strand or the antisense strand according to the nucleotide type and sequence of the sense strand or antisense strand in the double-stranded siRNA; wherein the linking of each nucleoside monomer comprises a four-step reaction of deprotection, coupling, capping, and oxidation or sulfurization, thus obtaining a sense strand linked to the solid phase support and an antisense strand linked to the solid phase support; contacting the compound as shown by Formula (321) with the sense strand linked to the solid phase support or the antisense strand linked to the solid phase support under coupling reaction condition in the presence of a coupling agent, thereby linking the compound as shown by Formula (321) to the sense strand or the antisense strand; wherein the compound as shown by Formula (321) is a compound in which R4 comprises a phosphoramidite group as the first functional group; removing the protecting groups and cleaving the solid phase support; respectively isolating and purifying to obtain the sense strand or the antisense strand of the siRNA; and annealing; wherein the sense strand or the antisense strand of the siRNA is linked to a conjugating molecule. 
     In some embodiments, the P atom in Formula A59 is linked to the 3′ terminal of the sense strand of the siRNA, and the method for preparing the siRNA conjugate as shown by Formula (308) comprises: 
     (1) removing the hydroxy protecting group R k  in the compound as shown by Formula (321) (wherein the compound as shown by Formula (321) is a compound in which R 4  comprises a first functional group and a second function group, the first functional group comprises a protected hydroxy OR k , and the second function group has a structure as shown by Formula (C1′) or (C3′)); and contacting the deprotected product with a nucleoside monomer to obtain a nucleoside monomer linked to a solid phase support via the conjugating molecule under a coupling reaction condition in the presence of a coupling agent; 
     (2) starting from the nucleoside monomer linked to the solid phase support via the conjugating molecule, synthesizing the sense strand of the siRNA in the direction from 3′ to 5′ by a solid phase phosphoramidite synthesis; 
     (3) synthesizing the antisense strand of the siRNA by a solid phase phosphoramidite synthesis method; and (4) isolating the sense strand and the antisense strand of the siRNA, and annealing the same to obtain the siRNA conjugate as shown by Formula (308). 
     In step (1), the method for removing the protecting group R k  in the compound as shown by Formula (321) comprises contacting the compound as shown by Formula (321) with a deprotection agent under a deprotection condition. The deprotection condition comprises a temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 30-300 seconds, and in some embodiments, 50-150 seconds. The deprotection agent may be selected from one or more of trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, and monochloroacetic acid, and in some embodiments, the deprotection agent is dichloroacetic acid. The molar ratio of the deprotection agent to the compound as shown by Formula (321) may be 10:1 to 1000:1, and in some embodiments, 50:1 to 500:1. 
     The coupling reaction condition and the coupling agent may be any conditions and agents suitable for the above coupling reaction. In some embodiments, the same condition and agent as those of the coupling reaction in the solid phase synthesis method may be used. 
     In some embodiments, the coupling reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C. The molar ratio of the compound as shown by Formula (321) to the nucleoside monomer may be 1:1 to 1:50, and in some embodiments, 1:2 to 1:5. The molar ratio of the compound as shown by Formula (321) to the coupling agent may be 1:1 to 1:50, and in some embodiments, 1:3 to 1:10. The reaction time may be 200-3000 seconds, and in some embodiments, 500-1500 seconds. The coupling agent may be selected from one or more of 1H-tetrazole, 5-ethylthio-1H-tetrazole and 5-benzylthio-1H-tetrazole, and in some embodiments, is 5-ethylthio-1H-tetrazole. The organic solvent may be selected from one or more of anhydrous acetonitrile, anhydrous DMF and anhydrous dichloromethane, and in some embodiments, is anhydrous acetonitrile. The amount of the organic solvent may be 3-50 L/mol, and in some embodiments, 5-20 L/mol, with respect to the compound as shown by Formula (321). 
     In step (2), a sense strand SS of the second siRNA conjugate is synthesized in the direction from 3′ to 5′ by the phosphoramidite nucleic acid solid phase synthesis method, starting from the nucleoside monomer linked to the solid phase support via the conjugating molecule prepared in the above steps. In this case, the conjugating molecule is linked to 3′terminal of the resultant sense strand. In this case, the conjugating molecule is linked to 3′terminal of the resultant sense strand. 
     Other conditions for the solid phase synthesis in steps (2) and (3), comprising the deprotection condition for the nucleoside monomer, the type and amount of the deprotection agent, the coupling reaction condition, the type and amount of the coupling agent, the capping reaction condition, the type and amount of the capping agent, the oxidation reaction condition, the type and amount of the oxidation agent, the sulfurization reaction condition, and the type and amount of the sulfurization agent, adopt various conventional agents, amounts, and conditions in the art. 
     For instance, in some embodiments, the solid phase synthesis in steps (2) and (3) may use the following conditions: 
     The deprotection condition for the nucleoside monomer comprises a temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 30-300 seconds, and in some embodiments, 50-150 seconds. The deprotection agent may be selected from one or more of trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, and monochloroacetic acid, and in some embodiments, the deprotection agent is dichloroacetic acid. The molar ratio of the deprotection agent to the protecting group 4,4′-dimethoxytrityl on the solid phase support is 2:1 to 100:1, and in some embodiments, is 3:1 to 50:1. 
     The coupling reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C. The molar ratio of the nucleic acid sequence linked to the solid phase support to the nucleoside monomer is 1:1 to 1:50, and in some embodiments, is 1:5 to 1:15. The molar ratio of the nucleic acid sequence linked to the solid phase support to the coupling agent is 1:1 to 1:100, and in some embodiments, is 1:50 to 1:80. The selection of the reaction time and the coupling agent can be same as above. 
     The capping reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 5-500 seconds, and in some embodiments, 10-100 seconds. The selection of the capping agent can be same as above. The molar ratio of the total amount of the capping agent to the nucleic acid sequence linked to the solid phase support may be 1:100 to 100:1, and in some embodiments, is 1:10 to 10:1. In the case where the capping agent uses equimolar acetic anhydride and N-methylimidazole, the molar ratio of the acetic anhydride to the N-methylimidazole and the nucleic acid sequence linked to the solid phase support may be 1:1:10 to 10:10:1, and in some embodiments, is 1:1:2 to 2:2:1. 
     The oxidation reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 1-100 seconds, and in some embodiments, 5-50 seconds. In some embodiments, the oxidation agent is iodine (in some embodiments, provided as iodine water). The molar ratio of the oxidation agent to the nucleic acid sequence linked to the solid phase support in the coupling step may be 1:1 to 100:1, and in some embodiments, is 5:1 to 50:1. In some embodiments, the oxidation reaction is performed in a mixed solvent in which the ratio of tetrahydrofuran:water:pyridine is 3:1:1 to 1:1:3. The sulfurization reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 50-2000 seconds, and in some embodiments, 100-1000 seconds. In some embodiments, the sulfurization agent is xanthane hydride. The molar ratio of the sulfurization agent to the nucleic acid sequence linked to the solid phase support in the coupling step is 10:1 to 1000:1, and in some embodiments, is 10:1 to 500:1. In some embodiments, the sulfurization reaction is performed in a mixed solvent in which the ratio of acetonitrile:pyridine is 1:3 to 3:1. 
     The method further comprises isolating the sense strand and the antisense strand of the siRNA after linking all nucleoside monomers and before the annealing. Methods for isolation are well-known to those skilled in the art and generally comprise cleaving the synthesized nucleotide sequence from the solid phase support, removing protecting groups on the bases, phosphate groups and ligands, purifying and desalting. 
     The conventional cleavage and deprotection methods in the synthesis of siRNAs can be used to cleave the synthesized nucleotide sequence from the solid phase support, and remove the protecting groups on the bases, phosphate groups and ligands. For example, contacting the resultant nucleotide sequence linked to the solid phase support with strong aqua; during deprotection, the protecting group YCOO— in groups A46-A54 is converted to a hydroxy, and thus the S 1  groups is converted to a corresponding Mi group, providing the siRNA conjugate as shown by Formula (308); wherein the strong aqua may be aqueous ammonia of a concentration of 25-30% by weight. The amount of the strong aqua may be 0.2 ml/μmol-0.8 ml/μmol with respect to the target siRNA. 
     When there is at least one 2′-TBDMS protection on the synthesized nucleotide sequence, the method further comprises contacting the nucleotide sequence removed from the solid phase support with triethylamine trihydrofluoride to remove the 2′-TBDMS protection. In this case, the resultant target siRNA sequence comprises the corresponding nucleoside having free 2′-hydroxy. The amount of pure triethylamine trihydrofluoride is 0.4 ml/μmol-1.0 ml/μmol with respect to the target siRNA sequence. As such, the siRNA conjugate as shown by Formula (308) may be obtained. 
     Methods for purification and desalination are well-known to those skilled in the art. For example, nucleic acid purification may be performed using a preparative ion chromatography purification column with a gradient elution of NaBr or NaCl; after collection and combination of the product, the desalination may be performed using a reverse phase chromatography purification column. 
     The non-bridging oxygen atom or sulfur atom in the phosphodiester bond or phosphorothioate diester bond between the nucleotides in the resultant siRNA conjugate as shown by Formula (308) substantially binds to a sodium ion, and the siRNA conjugate as shown by Formula (308) is substantially present in the form of a sodium salt. The well-known ion-exchange methods may be used, in which the sodium ion may be replaced with hydrogen ion and/or other cations, thereby providing other forms of siRNA conjugates as shown by Formula (308). The cations are as described above. 
     During synthesis, the purity and molecular weight of the nucleic acid sequence may be determined at any time. In order to better control the synthesis quality, such detection methods are well-known to those skilled in the art. For example, the purity of the nucleic acid may be detected by ion exchange chromatography, and the molecular weight may be determined by liquid chromatography-mass spectrometry (LC-MS). 
     Methods for annealing are also well-known to those skilled in the art. For example, the synthesized sense strand (S strand) and antisense strand (AS strand) may be simply mixed in water for injection at an equimolar ratio, heated to 70-95° C., and then cooled at room temperature to form a double-stranded structure via hydrogen bond. As such, the siRNA conjugate as shown by Formula (308) may be obtained. 
     After obtaining the siRNA conjugate, in some embodiments, the siRNA conjugate as shown by Formula (308) thus synthesized can also be characterized by the means such as molecular weight detection using the methods such as liquid chromatography-mass spectrometry, to confirm that the synthesized siRNA conjugate is the designed siRNA conjugate as shown by Formula (308) of interest, and the sequence of the synthesized siRNA is the sequence of the siRNA sequence desired to be synthesized, for example, is one of the sequences listed in Tables 1. 
     The compound as shown by Formula (321) may be prepared by the following method comprising: contacting a compound as shown by Formula (313) with a cyclic anhydride in an organic solvent under esterification reaction condition in the presence of a base and an esterification catalyst; and isolating the compound as shown by Formula (321) by ion exchange: 
     
       
         
         
             
             
         
       
     
     wherein the definitions and options of n1, n3, m1, m2, m3, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , L 1 , and S 1  are respectively as described above; 
     R 6  is a group for providing R 4  of Formula (321). In some embodiments, R 6  comprises a structure as shown by Formula (A61): 
     
       
         
         
             
             
         
       
     
     wherein, R i  is any group capable of linking to the N atom on the nitrogenous backbone, linking to R k O and linking to a free hydroxy; and R k  is a hydroxy protecting group. In this case, the compound as shown by Formula (321) is obtained, wherein R 4  comprises a first functional group as a hydroxy protecting group and a second functional group comprising a group as shown by Formula (C1) or (C2). 
     The esterification reaction condition comprises a reaction temperature of 0-100° C. and a reaction time of 8-48 hours. In some embodiments, the esterification reaction condition comprises a reaction temperature of 10-40° C. and a reaction time of 20-30 hours. 
     In some embodiments, the organic solvent comprises one or more of an epoxy solvent, an ether solvent, a haloalkane solvent, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diisopropylethylamine. In some embodiments, the epoxy solvent is dioxane and/or tetrahydrofuran, the ether solvent is diethyl ether and/or methyl tertbutyl ether, and the haloalkane solvent is one or more of dichloromethane, trichloromethane and 1,2-dichloroethane. In some embodiments, the organic solvent is dichloromethane. The amount of the organic solvent is 3-50 L/mol, and in some embodiments, 5-20 L/mol, with respect to the compound as shown by Formula (313). 
     In some embodiments, the cyclic anhydride is one of succinic anhydride, glutaric anhydride, adipic anhydride or pimelic anhydride, and in some embodiments, the cyclic anhydride is succinic anhydride. The molar ratio of the cyclic anhydride to the compound as shown by Formula (313) is 1:1 to 10:1, and in some embodiments, 2:1 to 5:1. 
     The esterification catalyst may be any catalyst capable of catalyzing esterification, for example, the catalyst may be 4-dimethylaminopyridine. The molar ratio of the catalyst to the compound as shown by Formula (313) is 1:1 to 10:1, and in some embodiments, 2:1 to 5:1. 
     In some embodiments, the base may be any inorganic base, organic base or a combination thereof. Considering solubility and product stability, the base may be, for example, tertiary amine. In some embodiments, the tertiary amine is triethylamine or N,N-diisopropylethylamine. The molar ratio of the tertiary amine to the compound as shown by Formula (313) is 1:1 to 20:1, and in some embodiments, is 3:1 to 10:1. 
     The ion exchange serves the function of converting the compound as shown by Formula (321) into a desired form of carboxylic acid or carboxylic salt and the methods of ion exchange are well-known to those skilled in the art. The above conjugating molecule in which the cation is M +  may be obtained by using suitable ion exchange solution and ion exchange condition, which is not described here in detail. In some embodiments, a triethylamine phosphate solution is used in the ion exchange reaction, and the concentration of the triethylamine phosphate solution is 0.2-0.8 M. In some embodiments, the concentration of the triethylamine phosphate solution is 0.4-0.6 M. In some embodiments, the amount of the triethylamine phosphate solution is 3-6 L/mol, and in further embodiment, 4-5 L/mol, with respect to the compound as shown by Formula (313). 
     The compound as shown by Formula (321) may be isolated from the reaction mixture using any suitable isolation methods. In some embodiments, the compound as shown by Formula (321) may be isolated by removal of solvent via evaporation followed by chromatography, for example, using the following two chromatographic conditions for the isolation: (1) normal phase purification of 200-300 mesh silica gel filler, and gradient elution of 1 wt % triethylamine in dichloromethane:methanol=100:18 to 100:20; or (2) reverse phase purification of C18 and C8 reverse phase filler, and gradient elution of methanol:acetonitrile=0.1:1 to 1:0.1. In some embodiments, the solvent may be directly removed to obtain a crude product of the compound as shown by Formula (321), which may be directly used in subsequent reactions. 
     In some embodiments, the method for preparing the compound as shown by Formula (321) further comprises: contacting the product obtained from the above ion exchanging reaction with a solid phase support containing amino or hydroxy in an organic solvent under condensation reaction condition in the presence of a condensing agent, a condensing catalyst and tertiary amine. In this case, the compound as shown by Formula (321) is obtained, wherein R 4  comprises a first functional group comprising a hydroxy protecting group and a second functional group having a structure as shown by Formula (Cl&#39;). 
     The solid phase support is one of the carriers used in solid phase synthesis of siRNA, some of which are well-known to those skilled in the art. For example, the solid phase support may be selected from the solid phase supports containing an active hydroxy or amino functional group. In some embodiments, the solid phase support is an amino resin or hydroxy resin. In some embodiments, the amino or hydroxy resin has the following parameters: particle size of 100-400 mesh, and surface amino or hydroxy loading of 0.2-0.5 mmol/g. The ratio of the compound as shown by Formula (321) to the solid phase support is 10-400 μmol compound per gram of solid phase support (μmol/g). In some embodiments, the ratio of the compound of Formula (321) to the solid phase support is 50-200 μmol/g. 
     The organic solvent may be any suitable solvent or mixed solvents known to those skilled in the art. In some embodiments, the organic solvent comprises one or more of acetonitrile, an epoxy solvent, an ether solvent, a haloalkane solvent, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diisopropylethylamine. In some embodiments, the epoxy solvent is dioxane and/or tetrahydrofuran, the ether solvent is diethyl ether and/or methyl tertbutyl ether, and the haloalkane solvent is one or more of dichloromethane, trichloromethane and 1,2-dichloroethane. In some embodiments, the organic solvent is acetonitrile. The amount of the organic solvent may be 20-200 L/mol, and in some embodiments, 50-100 L/mol, with respect to the compound as shown by Formula (321). 
     In some embodiments, the condensing agent may be benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBop), 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) and/or O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate. In some embodiments, the condensing agent is O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate. The molar ratio of the condensing agent to the compound as shown by Formula (321) is 1:1 to 20:1, and in some embodiments, 1:1 to 5:1. 
     In some embodiments, the tertiary amine is triethylamine and/or N,N-diisopropylethylamine, and in some embodiments, N,N-diisopropylethylamine. The molar ratio of the tertiary amine to the compound as shown by Formula (321) is 1:1 to 20:1, and in some embodiments, 1:1 to 5:1. 
     In some embodiments, the method for preparing the compound as shown by Formula (321) further comprises: contacting the resultant condensation product with a capping agent and an acylation catalyst in an organic solvent under capping reaction condition, and isolating the compound as shown by Formula (321). The capping reaction is used to remove any active functional group that does not completely react, so as to avoid producing unnecessary by products in subsequent reactions. The capping reaction condition comprises a reaction temperature of 0-50° C., and in some embodiments, 15-35° C., and a reaction time of 1-10 hours, and in some embodiments, 3-6 hours. The capping agent may be a capping agent used in solid phase synthesis of siRNA, and the capping agent used in solid phase synthesis of siRNA is well known to those skilled in the art. 
     In some embodiments, the capping agent is composed of a capping agent 1 (cap1) and a capping agent 2 (cap2). The cap1 is N-methylimidazole, and in some embodiments, provided as a mixed solution of N-methylimidazole in pyridine/acetonitrile, wherein the volume ratio of the pyridine to the acetonitrile is 1:10 to 1:1, and in some embodiments, 1:3 to 1:1. In some embodiments, the ratio of the total volume of the pyridine and acetonitrile to the volume of the N-methylimidazole is 1:1 to 10:1, and in some embodiments, 3:1 to 7:1. The capping agent 2 is acetic anhydride. In some embodiments, the capping agent 2 is provided as a solution of acetic anhydride in acetonitrile, wherein the volume ratio of the acetic anhydride to the acetonitrile is 1:1 to 1:10, and in some embodiments, 1:2 to 1:6. 
     In some embodiments, the ratio of the volume of the mixed solution of N-methylimidazole in pyridine/acetonitrile to the mass of the compound as shown by Formula (321) is 5 ml/g to 50 ml/g, and in some embodiments, 15 ml/g to 30 ml/g. The ratio of the volume of the solution of acetic anhydride in acetonitrile to the mass of the compound as shown by Formula (321) is 0.5 ml/g to 10 ml/g, and in some embodiments, 1 ml/g to 5 ml/g. 
     In some embodiments, the capping agent comprises equimolar acetic anhydride and N-methylimidazole. In some embodiments, the organic solvent comprises one or more of acetonitrile, an epoxy solvent, an ether solvent, a haloalkane solvent, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diisopropylethylamine. In some embodiments, the organic solvent is acetonitrile. The amount of the organic solvent may be 10-50 L/mol, and in some embodiments, 5-30 L/mol, with respect to the compound as shown by Formula (321). 
     In some embodiments, the acylation catalyst may be selected from any catalyst that may be used for esterification condensation or amidation condensation, such as alkaline heterocyclic compounds. In some embodiments, the acylation catalyst is 4-dimethylaminopyridine. The mass ratio of the catalyst to the compound as shown by Formula (321) may be 0.001:1 to 1:1, and in some embodiments, 0.01:1 to 0.1:1. 
     In some embodiments, the compound as shown by Formula (321) may be isolated from the reaction mixture using any suitable isolation methods. In some embodiments, the compound as shown by Formula (321) may be obtained by thoroughly washing with an organic solvent and filtering to remove unreacted reactants, excess capping agent and other impurities, wherein the organic solvent is selected from acetonitrile, dichloromethane, or methanol. In some embodiments, the organic solvent is acetonitrile. 
     In some embodiments, the preparation of the conjugating molecule as shown by Formula (321) comprises contacting a compound as shown by Formula (313) with a phosphorodiamidite in an organic solvent under coupling reaction condition in the presence of a coupling agent, and isolating the compound as shown by Formula (321). In this case, the compound as shown by Formula (321) is obtained, where R 4  comprises a first functional group comprising a hydroxy protecting group and a second functional group having a structure as shown by Formula (C3). 
     In some embodiments, the coupling reaction condition comprises a reaction temperature of 0-50° C., such as 15-35° C. The molar ratio of the compound as shown by Formula (313) to the phosphorodiamidite may be 1:1 to 1:50, such as 1:5 to 1:15. The molar ratio of the compound as shown by Formula (313) to the coupling agent may be 1:1 to 1:100, such as 1:50 to 80. The reaction time may be 200-3000 seconds, such as 500-1500 seconds. The phosphorodiamidite may be, for example, bis(diisopropylamino)(2-cyanoethoxy)phosphine, which may be commercially available or synthesized according to well-known methods in the art. The coupling agent is selected from one or more of 1H-tetrazole, 5-ethylthio-1H-tetrazole and 5-benzylthio-1H tetrazole, such as 5-ethylthio-1H-tetrazole. The coupling reaction may be performed in an organic solvent, and the organic solvent is selected from one or more of anhydrous acetonitrile, anhydrous DMF and anhydrous dichloromethane, such as anhydrous acetonitrile. The amount of the organic solvent may be 3-50 L/mol, such as 5-20 L/mol, with respect to the compound as shown by Formula (313). By performing the coupling reaction, the hydroxy in the compound as shown by Formula (313) reacts with the phosphorodiamidite to form a phosphoramidite group. In some embodiments, the solvent may be directly removed to obtain a crude product of the compound as shown by Formula (321), which may be directly used in subsequent reactions. 
     In some embodiments, the method for preparing the compound as shown by Formula (321) further comprises: contacting the isolated product with a solid phase support containing hydroxy in an organic solvent under coupling reaction condition in the presence of a coupling agent, followed by capping, oxidation, and isolation, to obtain the compound as shown by Formula (321). In this case, the compound as shown by Formula (321) is obtained, where R 4  comprises a first functional group comprising a hydroxy protecting group and a second functional group having a structure as shown by Formula (C3′). 
     In some embodiments, the solid phase support is a well-known solid phase support in the art for solid phase synthesis of a nucleic acid, such as a deprotected commercially available universal solid phase support (NittoPhase®HL UnyLinker™ 300 Oligonucleotide Synthesis Support, Kinovate Life Sciences, as shown by Formula B80): 
     
       
         
         
             
             
         
       
     
     A deprotection reaction is well-known in the art. In some embodiments, the deprotection condition comprises a temperature of 0-50° C., such as 15-35° C.; and a reaction time of 30-300 seconds, such as 50-150 seconds. The deprotection agent may be selected from one or more of trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, and monochloroacetic acid. In some embodiments, the deprotection agent is dichloroacetic acid. The molar ratio of the deprotection agent to the protecting group -DMTr(4,4′-dimethoxytrityl) on the solid phase may be 2:1 to 100:1, such as 3:1 to 50:1. By such deprotection, hydroxys with reactivity are obtained on the surface of the solid phase support, for facilitating the subsequent coupling reaction. 
     The coupling reaction condition and the coupling agent may be selected as above. By performing coupling reaction, the free hydroxys formed in the deprotection reaction reacts with the phosphoramidite groups, so as to form a phosphite ester linkage. 
     In some embodiments, the capping reaction condition comprises a reaction temperature of 0-50° C., such as 15-35° C., and a reaction time of 5-500 seconds, such as 10-100 seconds. The capping reaction is performed in the presence of a capping agent. The selection and amount of the capping agent are as above. 
     The oxidation reaction condition may comprise a temperature of 0-50° C., such as 15 35° C., and a reaction time of 1-100 seconds, such as 5-50 seconds. The oxidation agent may be, for example, iodine (in some embodiments, provided as iodine water). In some embodiments, the molar ratio of the oxidation agent to the nucleic acid sequence linked to the solid phase support is 1:1 to 100:1, such as 5:1 to 50:1. In some embodiments, the oxidation reaction is performed in a mixed solvent in which the ratio of tetrahydrofuran: water: pyridine is 3:1:1 to 1:1:3. 
     In some embodiments, R 6  is a group as shown by Formula B7 or B8: 
     
       
         
         
             
             
         
       
     
     wherein the definition of q 2  is as described above. 
     In this case, the compound as shown by Formula (313) may be prepared by the following method: contacting a compound as shown by Formula (314) with a compound as shown by Formula (A-1) or a compound as shown by Formula (A-2) in an organic solvent under amidation reaction condition in the presence of an agent for amidation condensation and tertiary amine, and isolating: 
     
       
         
         
             
             
         
       
     
     wherein the definitions and options of n1, n3, m1, m2, m3, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , L 1 , S 1 , q 2  and R k  are respectively as described above. 
     The amidation reaction condition may comprise a reaction temperature of 0-100° C. and a reaction time of 1-48 hours. In some embodiments, the amidation reaction condition comprises a reaction temperature of 10-40° C. and a reaction time of 2-16 hours. 
     In some embodiments, the organic solvent is one or more of an alcohol solvent, an epoxy solvent, an ether solvent, a haloalkane solvent, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diisopropylethylamine. In some embodiments, the alcohol solvent is one or more of methanol, ethanol and propanol, and in some embodiments, ethanol. In some embodiments, the epoxy solvent is dioxane and/or tetrahydrofuran. In some embodiments, the ether solvent is diethyl ether and/or methyl tertbutyl ether. In some embodiments, the haloalkane solvent is one or more of dichloromethane, trichloromethane and 1,2-dichloroethane. In some embodiments, the organic solvent is dichloromethane. The amount of the organic solvent is 3-50 L/mol, and in further embodiments, 3-20 L/mol, with respect to the compound as shown by Formula (314). 
     In some embodiments, the agent for amidation condensation is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 3-(Di ethoxypho sphoryl oxy)-1,2,3-b enzotri azin-4(3H)-one, 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, 2 ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, and in further embodiments, 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one. The molar ratio of the agent for amidation condensation to the compound as shown by Formula (314) may be 1:1 to 10:1, and in some embodiments, 2.5:1 to 5:1. 
     In some embodiments, the tertiary amine is triethylamine and/or N,N-diisopropylethylamine, and in further embodiments, N,N-diisopropylethylamine. The molar ratio of the tertiary to the compound as shown by Formula (314) is 3:1 to 20:1, and in some embodiments, is 5:1 to 10:1. 
     The compounds as shown by Formula (A-1) and Formula (A-2) may be prepared by any suitable methods. For example, when R k  is a DMTr group, the compound as shown by Formula (A-1) may be prepared by reacting calcium glycerate with DMTrCl. Similarly, the compound as shown by Formula (A-2) may be prepared by contacting 3-amino-1,2-propanediol with a cyclic anhydride and then reacting with DMTrCl, wherein the cyclic anhydride may have 4-13 carbon atoms, and in some embodiments, 4-8 carbon atoms. Those skilled in the art would readily understand that the selections of the cyclic anhydride correspond to different values for q 2  in the compound as shown by Formula (A-2). For example, when the cyclic anhydride is succinic anhydride, q 2 =1; when the cyclic anhydride is glutaric anhydride, q 2 =2, and so on. 
     In some variants, the compound as shown by Formula (313) can also be prepared by successively reacting the compound as shown by Formula (314) with the cyclic anhydride, 3-amino-1,2 propanediol, and DMTrCl. Those skilled in the art would readily understand that these variants would not affect the structure and function of the compound as shown by Formula (313), and these variants can be readily achieved by those skilled in the art on the basis of the above methods. 
     Similarly, the compound as shown by Formula (313) may be isolated from the reaction mixture by any suitable isolation methods. In some embodiments, the compound as shown by Formula (313) may be isolated by removal of solvent via evaporation followed by chromatography, for example, using the following two chromatographic conditions for isolation: (1) normal phase purification of 200-300 mesh silica gel filler, and gradient elution of petroleum ether:ethyl acetate:dichloromethane:N,N-dimethylformamide=1:1:1:0.5 1:1:1:0.6; and (2) reverse phase purification of C18 and C8 reverse phase fillers, and gradient elution of methanol:acetonitrile=0.1:1 to 1:0.1. In some embodiments, the solvent may be directly removed to obtain a crude product of the compound as shown by Formula (313), which may be directly used in subsequent reactions. 
     In some embodiments, the compound as shown by Formula (314) may be prepared by the following method comprising: contacting a compound as shown by Formula (320) with a compound as shown by Formula (316) in an organic solvent under under condensation reaction condition in the presence of an agent for amidation condensation and tertiary amine, and isolating: 
     
       
         
         
             
             
         
       
     
     wherein the definitions and options of n1, n3, m1, m2, m3, R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are respectively as described above. 
     The compound as shown by Formula (316) can be, such as, those disclosed in J. Am. Chem. Soc. 2014, 136, 16958-16961, or, the compounds as shown by Formula (316) may be prepared by those skilled in the art via various methods. For example, some compound as shown by Formula (316) may be prepared according to the methods as disclosed in Example 1 of U.S. Pat. No. 8,106,022 B2, which is incorporated herein by reference in its entirety. 
     In some embodiments, the condensation reaction condition comprises a reaction temperature of 0-100° C. and a reaction time of 0.1-24 hours. In some embodiments, the condensation reaction condition comprises a reaction temperature is 10-40° C. and a reaction time is 0.5-16 hours. 
     Considering the structure of the desired compound as shown by Formula (314), the molar ratio of the compound as shown by Formula (316) to the compound as shown by Formula (320) should be determined based on the sum of nl and n3 in Formula (320). In some embodiments, for example, when n1+n3=3, in order to ensure that the reaction is complete and not excessive, the molar ratio of the compound as shown by Formula (316) to the compound as shown by Formula (320) may be 3:1 to 3.5:1, and in some embodiments, is 3.01:1 to 3.15:1. 
     In some embodiments, the organic solvent is one or more of acetonitrile, an epoxy solvent, an ether solvent, a haloalkane solvent, dimethyl sulfoxide, N,N-dimethylformamide, and N,N-diisopropylethylamine. In some embodiments, the epoxy solvent is dioxane and/or tetrahydrofuran. In some embodiments, the ether solvent is diethyl ether and/or methyl tertbutyl ether. In some embodiments, the haloalkane solvent is one or more of dichloromethane, trichloromethane and 1,2-dichloroethane. In some embodiments, the organic solvent is acetonitrile. The amount of the organic solvent is 3-50 L/mol, and in some embodiments, 5-20 L/mol, with respect to the compound as shown by Formula (320). 
     In some embodiments, the agent for amidation condensation is benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride or 1-hydroxybenzotriazole, and in further embodiments, is a mixture of the benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate and the 1-hydroxybenzotriazole, wherein the benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBop) and the 1-hydroxybenzotriazole are equimolar. The molar ratio of the total agent for amidation condensation to the compound as shown by Formula (316) may be 1:1 to 3:1, and in some embodiments, is 1.05:1 to 1.5:1. 
     The tertiary amine may be N-methylmorpholine, triethylamine or N,N-diisopropylethylamine, and in some embodiments, N-methylmorpholine. The molar ratio of the tertiary amine to the compound as shown by Formula (316) may be 2:1 to 10:1, and in some embodiments, is 2:1 to 5:1. 
     Similarly, the compound as shown by Formula (314) may be isolated from the reaction mixture by any suitable isolation methods. In some embodiments, the compound as shown by Formula (314) is isolated by removal of solvent via evaporation followed by chromatography, for example, using the following two chromatographic conditions for isolation: (1) normal phase purification of 200-300 mesh silica gel filler, and gradient elution of dichloromethane:methanol=100:5 to 100:7; and (2) reverse phase purification of C18 and C8 reverse phase fillers, and gradient elution of methanol:acetonitrile=0.1:1 to 1:0.1. In some embodiments, the solvent is directly removed to obtain a crude product of the compound as shown by Formula (314), and the crude product can be directly used in subsequent reactions. 
     The compound as shown by Formula (320) may be commercially available, or obtained by those skilled in the art via the known methods. For example, in the case that m1=m2=m3=3, n1=1, n3=2, and R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are all H, the compound as shown by Formula (320) is commercially available from Alfa Aesar Inc. 
     The siRNA conjugate of the present disclosure may also be used in combination with other pharmaceutically acceptable excipients, which may be one or more of the various conventional formulations or compounds in the art. For details, please refer to the above description of the pharmaceutical compositions of the present disclosure. 
     Use of the siRNA, the Pharmaceutical Composition and the siRNA Conjugate of the Present Disclosure 
     In some embodiments, the present disclosure provides use of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate according to the present disclosure in the manufacture of a medicament for treating and/or preventing abnormal uric acid metabolism or a disease or a physiological condition caused by abnormal uric acid metabolism. In some embodiments, the disease or physiological condition caused by abnormal uric acid metabolism is hyperuricemia or gout. 
     In some embodiments, the present disclosure provides a method for preventing and/or treating abnormal uric acid metabolism or a disease or a physiological condition caused by abnormal uric acid metabolism, wherein the method comprises administering an effective amount of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure to a subject in need. In some embodiments, the disease or physiological condition caused by abnormal uric acid metabolism is hyperuricemia or gout. 
     It is possible to achieve the purpose of preventing and/or treating abnormal uric acid metabolism or the disease or physiological condition caused by abnormal uric acid metabolism based on a mechanism of RNA interference by administering the active ingredients of the siRNA of the present disclosure to the subject in need. Thus, the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure may be used for preventing and/or treating abnormal uric acid metabolism or the disease or physiological condition caused by abnormal uric acid metabolism, or for the manufacture of a medicament for preventing and/or treating abnormal uric acid metabolism or the disease or physiological condition caused by abnormal uric acid metabolism. In some embodiments, the abnormal uric acid metabolism, or the disease or physiological condition caused by abnormal uric acid metabolism is hyperuricemia or gout. 
     As used herein, the term “administration/administer” refers to the delivery of the siRNA, the pharmaceutical composition, and/or the siRNA conjugate of the present disclosure into a body of a subject by a method or a route that at least partly locates the siRNA, the pharmaceutical composition, and/or the siRNA conjugate of the present disclosure at a desired site to produce a desired effect. Suitable administration routes for the methods of the present disclosure comprise topical administration and systemic administration. In general, the topical administration results in the delivery of more siRNA conjugate to a particular site compared with the systemic circulation of the subject; whereas the systemic administration results in the delivery of the siRNA, the pharmaceutical composition, and/or the siRNA conjugate of the present disclosure to the substantial systemic circulation of the subject. Considering that the present disclosure can provide a means for preventing and/or treating the abnormal uric acid metabolism, or the disease or physiological condition caused by abnormal uric acid metabolism, in some embodiments, an administration mode capable of delivering drugs to liver is used. 
     The administration to a subject may be achieved by any suitable routes known in the art, including but not limited to, oral or parenteral route, such as intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, intratracheal administration (aerosol), pulmonary administration, nasal administration, rectal administration and topical administration (including buccal administration and sublingual administration). The administration frequency may be once or more times daily, weekly, biweekly, triweekly, monthly or annually. 
     The dose of the siRNA, the pharmaceutical composition, or the second siRNA conjugate of the present disclosure may be a conventional dose in the art, and the dose may be determined according to various parameters, especially age, weight and gender of a subject. Toxicity and efficacy may be measured in cell cultures or experimental animals by standard pharmaceutical procedures, for example, by determining LD 50  (the lethal dose that causes 50% population death), and ED 50  (the dose that can cause 50% of the maximum response intensity in a quantitative response, and that causes 50% of the experimental subjects to have a positive response in a qualitative response). The dose range for human may be derived based on the data obtained from cell culture analysis and animal studies. 
     When administrating the siRNA, the pharmaceutical composition or the siRNA conjugate of the present disclosure, for example, to male or female C57BL/6J mice of 6-12 weeks old and 18-25 g body weight or ob/ob mice of 30-45 g, and calculating based on the amount of the siRNA: (i) for the siRNA conjugate, the dosage of the siRNA thereof may be 0.001-100 mg/kg body weight, and in further embodiments, is 0.01-50 mg/kg body weight, and in some embodiments, is 0.05-20 mg/kg body weight, in some another embodiments is 0.1-15 mg/kg body weight, and in some another embodiments, is 0.1-10 mg/kg body weight; and (ii) for a pharmaceutical composition formed by an siRNA and a pharmaceutically acceptable carrier, the dosage of the siRNA thereof may be 0.001-50 mg/kg body weight, in some embodiments, is 0.01-10 mg/kg body weight, in some embodiments, is 0.05-5 mg/kg body weight, and in some embodiments, is 0.1-3 mg/kg body weight. 
     In some embodiments, the present disclosure provides a method for inhibiting expression of a XO gene in a cell. The method comprises contacting an effective amount of the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure with the cell, introducing the siRNA and/or the pharmaceutical composition and/or the siRNA conjugate of the present disclosure into the cell, and achieving the purpose of inhibiting the expression of the XO gene in the cell through a mechanism of RNA interference. The cell may be selected from SMIVIC-7721, CAL-27, Huh7 and other cancer cell lines or isolated primary hepatocytes. In some embodiments, the cells are CAL-27 cells. 
     In the case where the expression of the XO in the cell is inhibited by using the method provided by the present disclosure, the amount of the siRNA in the modified siRNA, the pharmaceutical composition, and/or the siRNA conjugate provided is typically: an amount sufficient to reduce the expression of the target gene and result in an extracellular concentration of 1 pM to 1 μM, or 0.01 nM to 100 nM, or 0.05 nM to 50 nM or 0.05 nM to about 5 nM on the surface of the target cell. 
     The amount required to achieve this local concentration will vary with various factors, including the delivery method, the delivery site, the number of cell layers between the delivery site and the target cells or tissues, the delivery route (topical or systemic), etc. The concentration at the delivery site may be significantly higher than that on the surface of the target cells or tissues. 
     Kit 
     The present disclosure provides a kit, wherein the kit comprises an effective amount of at least one of the modified siRNA, the pharmaceutical composition, and the siRNA conjugate of the present disclosure. 
     In some embodiments, the kit disclosed herein may provide a modified siRNA in one container. In some embodiments, the kit of the present disclosure may comprise a container providing pharmaceutically acceptable excipients. In some embodiments, the kit may further comprise additional ingredients, such as stabilizers or preservatives. In some embodiments, the kit herein may comprise at least one additional therapeutic agent in other container than the container providing the modified siRNA herein. In some embodiments, the kit may comprise an instruction for mixing the modified siRNA with the pharmaceutically acceptable carrier and/or adjuvants or other ingredients (if any). 
     In the kit of the present disclosure, the modified siRNA and the pharmaceutically acceptable carrier and/or the adjuvants as well as the modified siRNA, the pharmaceutical composition, and/or the siRNA conjugate and/or the pharmaceutically acceptable adjuvants may be provided in any form, e.g., in a liquid form, a dry form, or a lyophilized form. In some embodiments, the modified siRNA and the pharmaceutically acceptable carrier and/or the adjuvants as well as the pharmaceutical composition and/or the siRNA conjugate and optional pharmaceutically acceptable adjuvants are substantially pure and/or sterile. In some embodiments, sterile water may be provided in the kit of the present disclosure. 
     Hereinafter, the present disclosure will be further described by examples, but is not limited thereto in any respect. 
     EXAMPLES 
     Unless otherwise specified, the agents and culture media used in following examples are all commercially available, and the procedures used such as nucleic acid electrophoresis and real-time PCR are all performed according to methods described in Molecular Cloning (Cold Spring Harbor Laboratory Press (1989)). 
     C57BL/6N mice: 6-8 weeks old, purchased from Beijing Charles River Laboratory Animal Technology Co., Ltd., hereinafter referred to as C57 mice. 
     Unless otherwise specified, ratios of reagents provided below are all calculated by volume ratio (v/v). 
     Unless otherwise specified, the following experimental data of the in vivo/in vitro are all expressed as X±SEM, and the data analysis is carried out by using Graphpad prism5.0 statistical analysis software. 
     Preparation Example 1 
     Preparation of siRNA Conjugate L10-siXOi1M1S 
     In this preparation example, the siRNA conjugate L10-siXOi1M1S was synthesized. The siRNA conjugate is an siRNA conjugate formed after a L L-9 conjugating molecule is conjugated with an siRNA with a number of siXOi1M1S. See Table 3 for the sequence of the conjugated siRNA in the siRNA conjugate. 
     (1-1) Synthesis of Compound L-10 
     The compound L-10 was synthesized according to the following method: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     (1-1-1) Synthesis of GAL-5 (A Terminal Segment of the Conjugating Molecule) 
     
       
         
         
             
             
         
       
     
     (1-1-1a) Synthesis of GAL-2 
     100.0 g of GAL-1 (N-acetyl-D-galactosamine hydrochloride, CAS No.: 1772-03-8, purchased from Ningbo Hongxiang Bio-Chem Co., Ltd., 463.8 mmol) was dissolved in 1000 ml of anhydrous pyridine, to which 540 ml of acetic anhydride (purchased from Enox Inc., 5565.6 mmol) was added in an ice water bath to react under stirring at room temperature for 1.5 hours. The resultant reaction solution was poured into 10 L of ice water and subjected to suction filtration under reduced pressure. The residue was washed with 2 L of ice water, and then added with a mixed solvent of acetonitrile/toluene (v/v ratio=1:1) until completely dissolved. The solvent was removed by evaporation to give 130.0 g of product GAL-2 as a white solid. 
     (1-1-1b) Synthesis of GAL-3 
     GAL-2 (35.1 g, 90.0 mmol) obtained in step (1-1-1a) was dissolved in 213 ml of anhydrous 1,2-dichloroethane, to which 24.0 g of TMSOTf (CAS No.: 27607-77-8, purchased from Macklin Inc., 108.0 mmol) was added under an ice water bath and nitrogen protection to react at room temperature overnight. 
     400 ml of dichloromethane was added to the reaction solution for dilution, filtered with diatomite, and then added with 1 L of saturated aqueous sodium bicarbonate solution and stirred evenly. An organic phase was isolated. An aqueous phase remained was extracted twice, each with 300 ml of dichloroethane, and all organic phases were combined and washed with 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated brine, respectively. The organic phase resulted from washing was isolated and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 26.9 g of product GAL-3 as a light yellow viscous syrup. (1-1-1c) Synthesis of GAL-4 
     GAL-3 (26.9 g, 81.7 mmol) obtained in step (1-1-1b) was dissolved in 136 ml of anhydrous 1,2-dichloroethane, added with 30 g of dry 4 Å molecular sieve powder followed by 9.0 g of 5-hexen-1-ol (CAS No.: 821-41-0, purchased from Adamas-beta Inc., 89.9 mmol), and stirred at room temperature for 30 minutes. 9.08 ml of TMSOTf (40.9 mmol) was added in an ice bath and nitrogen protection to react under stirring at room temperature overnight. The 4 Å molecular sieve powder was removed by filtration. The filtrate was added with 300 ml of dichloroethane for dilution, filtered with diatomite, and then added with 500 ml of saturated aqueous sodium bicarbonate solution and stirred for 10 minutes for washing. An organic phase was isolated. An aqueous phase was extracted once with 300 ml of dichloroethane. All organic phases were combined and washed with 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated brine respectively. The organic phase resulted from the washing was isolated and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give 41.3 g of product GAL-4 as a yellow syrup, which was directly used in the next oxidation reaction without purification. 
     (1-1-1d) Synthesis of GAL-5 
     GAL-4 (14.9 g, 34.7 mmol) obtained according to the method described in step (1-1-1c) was dissolved in a mixed solvent of 77 ml of dichloromethane and 77 ml of acetonitrile, added with 103 ml of deionized water and 29.7 g of sodium periodate (CAS No.: 7790-28-5, purchased from Aladdin Inc., 138.8 mmol) respectively, and stirred in an ice bath for 10 minutes. Ruthenium trichloride (CAS No.: 14898-67-0, purchased from Energy Chemical, 238 mg, 1.145 mmol) was added to react at room temperature overnight. The resultant reaction solution was diluted by adding 300 ml of water under stirring, and adjusted to a pH of about 7.5 by adding saturated sodium bicarbonate. An organic phase was isolated and discarded. An aqueous phase was extracted three times, each with 200 ml of dichloromethane, and the organic phase resulted from the extraction was discarded. The aqueous phase resulted from the extraction was adjusted to a pH of about 3 with citric acid solids and extracted three times, each with 200 ml of dichloromethane, and the resultant organic phases were combined and dried with anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure to give 6.85 g of product GAL-5 as a white foamy solid.  1 H NMR (400 MHz, DMSO) δ 12.01 (br, 1H), 7.83 (d, J=9.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.96 (dd, J=11.2, 3.2 Hz, 1H), 4.49 (d, J=8.4 Hz, 1H), 4.07-3.95 (m, 3H), 3.92-3.85 (m, 1H), 3.74-3.67 (m, 1H), 3.48-3.39 (m, 1H), 2.20 (t, J=6.8 Hz, 2H), 2.11 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.77 (s, 3H), 1.55-1.45 (m, 4H). 
     (1-1-2) Synthesis of L-8 
     
       
         
         
             
             
         
       
     
     J-0 (9.886 g, 52.5 mmol, purchased from AlfaAesar) and GAL-5 (72.819 g, 162.75 mmol, obtained by combining the products of multiple batches) obtained in step (1-1-1d) were dissolved in 525 ml of dichloromethane, added with diisopropylethylamine (DIEA, 44.782 g, 346.50 mmol), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBop, 90.158 g, 173.25 mmol) and hydroxybenzotriazole (HOBt, 23.410 g, 173.25 mmol) to react at room temperature for 4 hours, and then added with 20 ml of saturated sodium bicarbonate and 200 ml of saturated brine for washing. An aqueous phase was extracted twice, each with 100 ml of dichloromethane, and the resultant organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude product. The crude product was purified by using a normal phase silica gel column (200-300 mesh). The column was added with 10 wt % triethylamine for neutralizing the acidity of silica gel and equilibrated with 1 wt % triethylamine, and eluted with a gradient elution of dichloromethane:methanol=100:30 to 100:40. The eluate was collected, and the solvent was removed by evaporation under reduced pressure to give 38.8 g of pure product L-8.  1 H NMR (400 MHz, DMSO) δ 7.84 (d, J=9.0 Hz, 3H), 7.27-7.23 (m, 1H), 7.13-7.18 (m, 1H), 5.22 (d, J=3.1 Hz, 3H), 4.97 (dd, J=11.3, 3.1 Hz, 3H), 4.48 (d, J=8.4 Hz, 3H), 4.09-3.98 (m, 9H), 3.88 (dd, J=19.3, 9.3 Hz, 3H), 3.75-3.66 (m, 3H), 3.44-3.38 (m, 3H), 3.17-3.30 (m, 4H), 3.10-2.97 (m, 4H), 2.35-2.20 (m, 6H), 2.15-2.08 (m, 9H), 2.07-1.98 (m, 13H), 1.94-1.87 (m, 9H), 1.81-1.74 (m, 9H), 1.65-1.42 (m, 18H). MS m/z: C 85 H 119 N 7 O 30 , [M+H] + , called: 1477.59, meaasured: 1477.23. 
     (1-1-3a) Synthesis of A-1 
     
       
         
         
             
             
         
       
     
     DMTrC1 (4,4′-dimethoxytrityl chloride, 101.65 g, 300 mmol) was dissolved in 1000 ml of anhydrous pyridine, and added with calcium DL-glycerate hydrate (28.63 g, 100 mmol) to react at 45° C. for 20 hours. The reaction solution was filtered. The residue was rinsed with 200 ml of DCM, and the filtrate was concentrated to dryness under reduced pressure. The residue was redissolved in 500 ml of dichloromethane and washed twice, each with 200 ml of 0.5 M triethylamine phosphate (pH=7-8). An aqueous phase isolated was extracted twice, each with 200 ml of dichloromethane. All organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The solvent was removed by evaporation under reduced pressure, and the residue was purified by using a normal phase silica gel column (200-300 mesh) which was eluted with a gradient elution of petroleum ether:ethyl acetate:dichloromethane:methanol=1:1:1:0.35 to 1:1:1:0.55. The eluate was collected, and the solvent was removed by evaporation under reduced pressure. The residue was redissolved in 600 ml of dichloromethane, and washed once with 200 ml of 0.5 M triethylamine phosphate. The aqueous phase isolated was extracted once with 200 ml of dichloromethane. All organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The solvent was removed by evaporation under reduced pressure and overnight under reduced pressure in a vacuum oil pump to give 50.7 g of product A-1 as a white solid.  1 H NMR (400 MHz, DMSO-d6) δ 7.46 (ddd, J=6.5, 2.3, 1.1 Hz, 1H), 7.40-7.28 (m, 7H), 6.89-6.81 (m, 4H), 4.84 (d, J=5.0 Hz, 1H), 4.36-4.24 (m, 1H), 4.29 (s, 6H), 3.92 (dd, J=12.4, 7.0 Hz, 1H), 3.67 (dd, J=12.3, 7.0 Hz, 1H), 2.52 (q, J=6.3 Hz, 6H), 1.03 (t, J=6.3 Hz, 9H). MS m/z: C 24 H 23 O 6 , [M−H] − , called: 407.15, measured: 406.92. 
     (1-1-3b) Synthesis of L-7 
     
       
         
         
             
             
         
       
     
     L-8 (40 g, 27.09 mmol, obtained by combining the products of multiple batches) obtained in step (1-1-2) and A-1 (41.418 g, 81.27 mmol) obtained in step (1-1-3a) were mixed and dissolved in 271 ml of dichloromethane, added with 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, 24.318 g, 81.37 mmol), and further added with diisopropylethylamine (21.007 g, 162.54 mmol) to react under stirring at 25° C. for 1.5 hours. An organic phase was washed with 800 ml of saturated sodium bicarbonate. An aqueous phase isolated was extracted three times, each with 50 ml of dichloromethane. The organic phase was washed with 150 ml of saturated brine, and the aqueous phase was extracted once with 50 ml of dichloromethane. The resultant organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was foam-dried in a vacuum oil pump overnight to give a crude product. The crude product was subjected to a column purification. The column was filled with 2 kg of normal phase silica gel (200-300 mesh), added with 200 ml of triethylamine for neutralizing the acidity of the silica gel, equilibrated with petroleum ether containing lwt % triethylamine, and eluted with a gradient elution of petroleum ether:ethyl acetate:dichloromethane:N,N-dimethylformamide=1:1:1:0.5 to 1:1:1:0.6. The eluate was collected, and the solvent was removed by evaporation under reduced pressure to give 40.4 g of pure product L-7.  1 H NMR (400 MHz, DMSO) δ 7.90-7.78 (m, 4H), 7.75-7.64 (m, 1H), 7.38-7.18 (m, 9H), 6.91-6.83 (m, 4H), 5.25-5.10 (m, 4H), 4.97 (dd, J=11.2, 3.2 Hz, 3H), 4.48-4.30 (m, 4H), 4.02 (s, 9H), 3.93-3.84 (m, 3H), 3.76-3.66 (m, 9H), 3.45-3.35 (m, 3H), 3.24-2.98 (m, 10H), 2.30-2.20 (m, 2H), 2.11-1.88 (m, 31H), 1.80-1.40 (m, 28H). MS m/z: C 90 H 128 N 7 O 35 , [M-DMTr] + , called: 1564.65, measured: 1564.88. 
     (1-1-4) Synthesis of L-9 
     
       
         
         
             
             
         
       
     
     L-7 (40 g, 21.4247 mmol) obtained in step (1-1-3b), succinic anhydride (4.288 g, 42.8494 mmol) and 4-dimethylaminopyridine (DMAP, 5.235 g, 42.8494 mmol) were mixed and dissolved in 215 ml of dichloromethane, further added with diisopropylethylamine (DIPEA, 13.845 g, 107.1235 mmol), and stirred at 25° C. for 24 hours. The reaction solution was washed with 800 ml of 0.5 M triethylamine phosphate. An aqueous phase was extracted three times, each with 5 ml of dichloromethane. All organic phases were combined, and the solvent was evaporated under reduced pressure to give a crude product. The crude product was subjected to a column purification. The column was filled with 1 kg normal phase silica gel (200-300 mesh), added with 1 wt % triethylamine for neutralizing the acidity of the silica gel, equilibrated with dichloromethane and eluted with a gradient elution of 1 wt % triethylamine-containing dichloromethane:methanol=100:18 to 100:20. The eluate was collected, and the solvent was evaporated under reduced pressure to give 31.0 g of pure product of L-9 conjugating molecule.  1 H NMR (400 MHz, DMSO) δ 8.58 (d, J=4.2 Hz, 1H), 7.94-7.82 (m, 3H), 7.41-7.29 (m, 5H), 7.22 (d, J=8.1 Hz, 5H), 6.89 (d, J=8.3 Hz, 4H), 5.49-5.37 (m, 1H), 5.21 (d, J=3.0 Hz, 3H), 4.97 (d, J=11.1 Hz, 3H), 4.49 (d, J=8.2 Hz, 3H), 4.02 (s, 9H), 3.88 (dd, J=19.4, 9.4 Hz, 3H), 3.77-3.65 (m, 9H), 3.50-3.39 (m, 6H), 3.11-2.90 (m, 5H), 2.61-2.54 (m, 4H), 2.47-2.41 (m, 2H), 2.26-2.17 (m, 2H), 2.15-1.95 (m, 22H), 1.92-1.84 (m, 9H), 1.80-1.70 (m, 10H), 1.65-1.35 (m, 17H), 1.31-1.19 (m, 4H), 0.96 (t, J=7.1 Hz, 9H). MS m/z: C 94 H 132 N 7 O 38 , [M-DMTr] + , called: 1664.72, measured: 1665.03. 
     (1-1-5) Synthesis of Compound L-10 
     
       
         
         
             
             
         
       
     
     In this step, the compound L-10 was prepared by linking the L-9 conjugating molecule to a solid phase support. 
     The L-9 conjugating molecule (22.751 g, 0.1126 mmol) obtained in step (1-1-4), O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU, 6.257 g, 16.5 mmol) and diisopropylethylamine (DIEA, 2.843 g, 22 mmol) were mixed and dissolved in 900 ml of acetonitrile, and stirred at room temperature for 5 minutes. Aminomethyl resin (88 g, 100-200 mesh, amino loading: 400 μmol/g, purchased from Tianjin Nankai HECHENG S&amp;T Co., Ltd.) was added into the reaction liquid. A reaction was performed on a shaker at 25° C. and 150 rpm/min for 18 hours, followed by filtration. The residue was rinsed twice, each with 300 ml of DCM, and rinsed three times, each with 300 ml of acetonitrile, and dried for 18 hours with a vacuum oil pump. Then a capping reaction was performed by adding starting materials (CapA, CapB, 4-dimethylaminopyridine (DMAP) and acetonitrile) according to the charge ratio shown in Table 2. A reaction was performed on a shaker at 25° C. and 150 rpm/min for 5 hours. The reaction liquid was filtrated. The residue was rinsed three times, each with 300 ml of acetonitrile, the solvent was evaporated to dryness, and the mixture was dried overnight under a reduced pressure with a vacuum oil pump to give 102 g of compound L-10 (i.e., the L-9 conjugating molecule linked to the solid phase support), with a loading of 90.8 μmol/g. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 The charge ratio of capping reaction 
               
            
           
           
               
               
               
               
               
            
               
                 Starting materials 
                 Amount 
                 Grade 
                 Lot No. 
                 Manufacturer 
               
               
                   
               
               
                 CapA 
                  1980 ml 
                 — 
                 — 
                 — 
               
               
                 CapB 
                   220 ml 
                 — 
                 — 
                 — 
               
               
                 DMAP 
                 1.100 g 
                 Analytical pure 
                 I1422139 
                 Aladdin 
               
               
                 Acetonitrile 
                   220 ml 
                 Spectroscopic pure 
                 O15161001 
                 CINC (Shanghai) Co., Ltd 
               
               
                   
               
            
           
         
       
     
     In the above table, CapA and CapB are solutions of capping agents. CapA is a solution of 20% by volume of N-methylimidazole in a mixture of pyridine/acetonitrile, wherein the volume ratio of the pyridine to the acetonitrile is 3: 5. CapB is a solution of 20% by volume of acetic anhydride in acetonitrile. 
     (1-2) Synthesis of Sense Strand of siRNA Conjugate L10-siXOi1M1S 
     Nucleoside monomers were linked one by one in the direction from 3′ to 5′ according to the arrangement sequence of nucleotides in the sense strand by the solid phase phosphoramidite method, starting the cycles from the Compound L-10 prepared in the above step. The linking of each nucleoside monomer comprised a four-step reaction of deprotection, coupling, capping, and oxidation or sulfurization. When two nucleotides are linked via a phosphoester, a four-step reaction of deprotection, coupling, capping, and oxidation was comprised during linking of the later nucleoside monomer. When two nucleotides are linked via a phosphorothioate, a four-step reaction of deprotection, coupling, capping, and sulfurization was comprised during linking of the later nucleoside monomer. The synthesis condition was given as follows. 
     The nucleoside monomers were provided in a 0.1 M acetonitrile solution. The condition for deprotection reaction in each step was identical, i.e., a temperature of 25° C., a reaction time of 70 seconds, a solution of dichloroacetic acid in dichloromethane (3% v/v) as a deprotection agent, and a molar ratio of the dichloroacetic acid to the protecting group 4,4′-dimethoxytrityl on the solid phase support of 5:1. 
     The condition for coupling reaction in each step was identical, comprising a temperature of 25° C., a molar ratio of the nucleic acid sequence linked to the solid phase support to the nucleoside monomers of 1:10, a molar ratio of the nucleic acid sequence linked to the solid phase support to a coupling agent of 1:65, a reaction time of 600 seconds, and 0.5 M acetonitrile solution of 5-ethylthio-1H-tetrazole (ETT) as a coupling agent. 
     The condition for capping reaction in each step was identical, comprising a temperature of 25° C. and a reaction time of 15 seconds. A capping agent was a mixed solution of Cap A and Cap B in a molar ratio of 1:1, and a molar ratio of the capping agent to the nucleic acid sequence linked to the solid phase support was 1:1:1 (anhydride:N-methylimidazole:the nucleic acid sequence linked to the solid phase support). 
     The condition for oxidation reaction in each step was identical, comprising a temperature of 25° C., a reaction time of 15 seconds, and 0.05 M iodine water as an oxidation agent. A molar ratio of iodine to the nucleic acid sequence linked to the solid phase support in the coupling step was 30:1. The reaction was carried out in a mixed solvent in which the ratio of tetrahydrofuran:water:pyridine was 3:1:1. 
     The condition for sulfurization reaction in each step was identical, comprising a temperature of 25° C., a reaction time of 300 seconds, and xanthane hydride as a sulfurization agent. A molar ratio of the sulfurization agent to the nucleic acid sequence linked to the solid phase support in the coupling step was 120:1. The reaction was carried out in a mixed solvent in which the ratio of acetonitrile:pyridine was 1:1. 
     After the last nucleoside monomer was linked, the nucleic acid sequence linked to the solid phase support was cleaved, deprotected, purified and desalted in turn, and then freeze-dried to obtain the sense strand, wherein, 
     The conditions for cleavage and deprotection were as follows: adding the synthesized nucleotide sequence linked to the support into 25 wt % aqueous ammonia to react for 16 hours at 55° C., wherein the aqueous ammonia was in an amount of 0.5 ml/ I lmol; filtering to remove the support, and concentrating the supernatant in vacuum to dryness. 
     The conditions for purification and desalination were as follows: purifying the nucleic acid by using a preparative ion chromatography column (Source 15Q) with a gradient elution of NaCl. Specifically, eluent A: 20 mM sodium phosphate (pH 8.1), solvent: water/acetonitrile=9:1 (v/v); eluent B: 1.5 M sodium chloride, 20 mM sodium phosphate (pH 8.1), solvent: water/acetonitrile=9:1 (v/v); elution gradient: eluent A:eluent B=100:0 to 50:50. The eluate was collected, combined and desalted by using a reverse phase chromatography purification column. The specific conditions comprised using a Sephadex column (filler: Sephadex-G25) for desalination and deionized water for eluting. 
     The detection method was as follows: determining the purity of the sense strand above by ion exchange chromatography (IEX-HPLC); and analyzing the molecular weight by Liquid Chromatography-Mass Spectrometry (LC-MS). The called value was 7584.5, and the measured value was 7584.0. The measured value was in conformity with the called value, indicating that a sense strand SS conjugated with L-9 conjugating molecule at 3′ terminal was synthesized. 
     (1-3) Synthesis of Antisense Strand of siRNA Conjugate L10-siXOi1M1S 
     The antisense strand of the siRNA conjugate L10-siXOf1M1S was synthesized by starting the cycles using a universal solid phase support (UnyLinker™ loaded NittoPhase®HL Solid Supports, Kinovate Life Sciences Inc.) according to the solid phase phosphoramidite method. The deprotection, coupling, capping, oxidation or sulfurization reaction conditions, cleavage and deprotection, purification and desalting conditions in the solid phase synthesis method were conducted under the same conditions as those in the synthesis of the sense strand. The residue was freeze-dried to obtain the antisense strand AS. 
     The purity of the antisense strand was detected by ion exchange chromatography (IEX-HPLC), and the molecular weight was analyzed by liquid chromatography-mass spectrometry (LC-MS). The measured value was in conformity with the called value, indicating that an antisense strand AS having a target sequence was synthesized. 
     (1-4) Synthesis of siRNA Conjugate L10-siXOi1M1S 
     For the siRNA conjugate L10-siXOi1M1S, the sense strand and the antisense strand were respectively dissolved in water for injection to give a solution of 40 mg/mL, mixed at an equimolar ratio, heated at 50° C. for 15 minutes, and then cooled at room temperature, such that an annealed product was obtained and then freeze-dried to obtain lyophilized powder. The siRNA conjugate was diluted to a concentration of 0.2 mg/mL with ultra-pure water (prepared by Milli-Q ultra-pure water instrument, with resistivity of 18.2 MΩ*cm (25° C.)). The molecular weight was measured by Liquid Chromatography-Mass Spectrometry (LC-MS, purchased from Waters Corp., model: LCT Premier). Since the measured value was in conformity with the called value, it was confirmed that the synthesized siRNA conjugate was the designed double stranded nucleic acid sequence of interest with the L-9 conjugating molecule. The structure thereof was as shown by Formula (403). The siRNA was the sequence shown in Table 3 corresponding to the siRNA conjugate L10-siXOi1M1S. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 siRNA conjugates 
               
            
           
           
               
               
               
               
               
            
               
                 Preparation 
                   
                   
                   
                   
               
               
                 Example 
                 siRNA 
                   
                   
                 SEQ 
               
            
           
           
               
               
               
               
            
               
                 No. 
                 conjugate 
                 Sequence direction 5′-3′ 
                 ID NO 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Preparation 
                 L10-siXOi1 
                 Sense 
                 GmsAmsUmGmCmUmAfUfAfAmAmGmA 
                 505 
               
               
                 Example 1 
                 M1S 
                 strand 
                 mAmCmAmAmCmUm 
                   
               
               
                   
                   
                 Antisense 
                 AmsGfsUmUmGmUfUmCmUmUmUmAm 
                 506 
               
               
                   
                   
                 strand 
                 UmAfGmCfAmUmCmsCmsUm 
                   
               
               
                   
               
               
                 Preparation 
                 L10-siXOk 
                 Sense 
                 CmsUmsUmGmCmUmCfUfGfAmAmGmU 
                 625 
               
               
                 Example 2 
                 1M1S 
                 strand 
                 mAmGmAmAmAmUm 
                   
               
               
                   
                   
                 Antisense 
                 AmsUfsUmUmCmUfAmCmUmUmCmAm 
                 626 
               
               
                   
                   
                 strand 
                 GmAfGmCfAmAmGmsCmsCm 
                   
               
               
                   
               
               
                 Comparison 
                 NC 
                 Sense 
                 UmsUmsCmUmCmCmGfAfAfCmGmUmGm 
                 721 
               
               
                 Preparation 
                   
                 strand 
                 UmCmAmCmGmUm 
                   
               
               
                 Example 3 
                   
                 Antisense 
                 AmsCfsGmUmGmAfCmAmCmGmUmUmC 
                 722 
               
               
                   
                   
                 strand 
                 mGfGmAfGmAmAmsCmsUm 
               
               
                   
               
            
           
         
       
     
     wherein, capital letters C, U, and A indicated the base composition of the nucleotides; the lowercase m indicated that the nucleotide adjacent to the left side of the letter m was a methoxy modified nucleotide; the lowercase f indicated that the nucleotide adjacent to the left side of the letter f was a fluoro modified nucleotide; and the lowercase letter s indicated that the two nucleotides adjacent to the left and right of the letter s were linked by phosphorothioate. 
     Preparation Example 2 and Comparison Preparation Example 3 
     According to the method of Preparation Example 1, the siRNA conjugate L10-siXOk1M1S and the comparison siRNA conjugate NC were further synthesized. The siRNAs contained in these siRNA conjugates had the sense strands and antisense strands corresponding to L10-siXOk1M1S and NC in Table 3. The only difference between the preparation methods was that the sequences of the sense strands and the antisense strands of the siRNA conjugate L10-siXOi1M1S were replaced by the sense strands and the antisense strands corresponding to L10-siXOk1M1S and NC in Table 3. 
     After preparation, the molecular weights of the prepared siRNA conjugate L10-siXOk1M1S and NC were detected according to the method of the Preparation Example 1, and the measured values were consistent with the called values, indicating that the synthesized siRNA conjugate was a target designed double-stranded nucleic acid sequence with the L-9 conjugating molecule. The structure thereof was as shown by Formula (403). The siRNAs contained in these siRNA conjugates were respectively the sequences corresponding to the siRNA conjugate L10-siXOk1M1S and NC in Table 3. 
     Preparation Examples 4-18 and Comparison Preparation Example 19 
     Synthesis of the siRNA Provided by the Present Disclosure 
     The sense strands or the antisense strands of the siRNA sequences listed in Table 4 were respectively synthesized by a solid phase synthesis method, and DEPC water was used to dissolve the mutually complementary sense strands and antisense strands in equimolar in Table 4, and then followed by annealing to obtain the following siRNAs provided by the present disclosure comprising siXOa1M1S, siXOb1M1S, siXOc1M1S, siXOd1M1S, siXOe1M1S, siXOf1M1S, siXOg1M1S, siXOh1M1S, siXOi1M1S, siXOj1M1S, siXOk1M1S, siXOl1M1S, siXOa0, siXOe0 and siXOf0, as well as the comparison siRNA CON-siXOf. The sequences of the above siRNAs were shown in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 siRNA sequences 
               
            
           
           
               
               
               
               
               
            
               
                 Preparation 
                   
                   
                   
                   
               
               
                 Example 
                   
                   
                   
                 SEQ 
               
            
           
           
               
               
               
               
            
               
                 No. 
                 No. 
                 Sequence direction 5′-3′ 
                 ID NO 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Preparation 
                 siXOa1 
                 Sense strand 
                 GmsAmsGmAmUmGmAfAfGfUmUmCmA 
                  25 
               
               
                 Example 
                 M1S 
                   
                 mAmGmAmAmUmAm 
                   
               
               
                 4 
                   
                 Antisense 
                 UmsAfsUmUmCmUfUmGmAmAmCmUmU 
                  26 
               
               
                   
                   
                 strand 
                 mCfAmUfCmUmCmsAmsAm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOb1 
                 Sense strand 
                 CmsAmsUmAmAmCmUfGfGfAmAmUmU 
                  85 
               
               
                 Example 
                 M1S 
                   
                 mUmGmUmAmAmUm 
                   
               
               
                 5 
                   
                 Anti sense 
                 AmsUfsUmAmCmAfAmAmUmUmCmCmA 
                  86 
               
               
                   
                   
                 strand 
                 mGfUmUfAmUmGmsUmsUm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOc1 
                 Sense strand 
                 CmsAmsUmUmAmUmCfAfCfAmAmUmU 
                 145 
               
               
                 Example 
                 M1S 
                   
                 mGmAmGmGmAmUm 
                   
               
               
                 6 
                   
                 Antisense 
                 AmsUfsCmCmUmCfAmAmUmUmGmUmG 
                 146 
               
               
                   
                   
                 strand 
                 mAfUmAfAmUmGmsGmsCm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOd1 
                 Sense strand 
                 GmsGmsAmUmCmUmCfUfCfUmCmAmG 
                 205 
               
               
                 Example 
                 M1S 
                   
                 mAmGmUmAmUmUm 
                   
               
               
                 7 
                   
                 Antisense 
                 AmsAfsUmAmCmUfCmUmGmAmGmAmG 
                 206 
               
               
                   
                   
                 strand 
                 mAfGmAfUmCmCmsUmsGm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOe1 
                 Sense strand 
                 AmsCmsAmUmGmGmAfCfAfAmCmUmG 
                 265 
               
               
                 Example 
                 M1S 
                   
                 mCmUmAmUmAmAm 
                   
               
               
                 8 
                   
                 Antisense 
                 UmsUfsAmUmAmGfCmAmGmUmUmGmU 
                 266 
               
               
                   
                   
                 strand 
                 mCfCmAfUmGmUmsGmsGm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOf1 
                 Sense strand 
                 UmsAmsGmCmAmAmGfCfUfCmUmCmA 
                 325 
               
               
                 Example 
                 M1S 
                   
                 mGmUmAmUmCmAm 
                   
               
               
                 9 
                   
                 Antisense 
                 UmsGfsAmUmAmCfUmGmAmGmAmGmC 
                 326 
               
               
                   
                   
                 strand 
                 mUfUmGfCmUmAmsGmsGm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOg1 
                 Sense strand 
                 AmsUmsAmAmGmGmUfUfAfCmUmUmG 
                 385 
               
               
                 Example 
                 M1S 
                   
                 mUmGmUmUmGmGm 
                   
               
               
                 10 
                   
                 Antisense 
                 CmsCfsAmAmCmAfCmAmAmGmUmAmA 
                 386 
               
               
                   
                   
                 strand 
                 mCfCmUfUmAmUmsCmsCm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOh1 
                 Sense strand 
                 GmsAmsAmAmAmUmCfAfCfCmUmAmU 
                 445 
               
               
                 Example 
                 M1S 
                   
                 mGmAmAmGmAmAm 
                   
               
               
                 11 
                   
                 Antisense 
                 UmsUfsCmUmUmCfAmUmAmGmGmUmG 
                 446 
               
               
                   
                   
                 strand 
                 mAfUmUfUmUmCmsAmsCm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOi1 
                 Sense strand 
                 GmsAmsUmGmCmUmAfUfAfAmAmGmA 
                 505 
               
               
                 Example 
                 M1S 
                   
                 mAmCmAmAmCmUm 
                   
               
               
                 12 
                   
                 Antisense 
                 AmsGfsUmUmGmUfUmCmUmUmUmAmU 
                 506 
               
               
                   
                   
                 strand 
                 mAfGmCfAmUmCmsCmsUm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOj1 
                 Sense strand 
                 GmsAmsAmCmAmAmCfUfCfCmUmUmU 
                 565 
               
               
                 Example 
                 M1S 
                   
                 mUmAmUmGmGmAm 
                   
               
               
                 13 
                   
                 Antisense 
                 UmsCfsCmAmUmAfAmAmAmGmGmAmG 
                 566 
               
               
                   
                   
                 strand 
                 mUfUmGfUmUmCmsUmsUm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOk1 
                 Sense strand 
                 CmsUmsUmGmCmUmCfUfGfAmAmGmU 
                 625 
               
               
                 Example 
                 M1S 
                   
                 mAmGmAmAmAmUm 
                   
               
               
                 14 
                   
                 Antisense 
                 AmsUfsUmUmCmUfAmCmUmUmCmAmG 
                 626 
               
               
                   
                   
                 strand 
                 mAfGmCfAmAmGmsCmsCm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOl1 
                 Sense strand 
                 CmsUmsUmCmUmUmUfGfCfCmAmUmC 
                 685 
               
               
                 Example 
                 M1S 
                   
                 mAmAmAmGmAmUm 
                   
               
               
                 15 
                   
                 Antisense 
                 AmsUfsCmUmUmUfGmAmUmGmGmCmA 
                 686 
               
               
                   
                   
                 strand 
                 mAfAmGfAmAmGmsAmsUm 
                   
               
               
                   
               
               
                 Preparation 
                 siXOa0 
                 Sense strand 
                 GAGAUGAAGUUCAAGAAUA 
                 723 
               
               
                 Example 
                   
                 Antisense 
                 UAUUCUUGAACUUCAUCUC 
                 724 
               
               
                 16 
                   
                 strand 
                   
                   
               
               
                   
               
               
                 Preparation 
                 siXOe0 
                 Sense strand 
                 ACAUGGACAACUGCUAUAA 
                 725 
               
               
                 Example 
                   
                 Antisense 
                 UUAUAGCAGUUGUCCAUGU 
                 726 
               
               
                 17 
                   
                 strand 
                   
                   
               
               
                   
               
               
                 Preparation 
                 siXOf0 
                 Sense strand 
                 UAGCAAGCUCUCAGUAUCA 
                 727 
               
               
                 Example 
                   
                 Antisense 
                 UGAUACUGAGAGCUUGCUA 
                 728 
               
               
                 18 
                 strand 
                   
                   
                   
               
               
                   
               
               
                 Comparison 
                 CON-siXOf 
                 Sense strand 
                 CUAGCAAGCUCUCAGUAUC 
                 729 
               
               
                 Preparation 
                   
                 Antisense 
                 GATACTGAGAGCTTGCTAG 
                 730 
               
               
                 Example 
                   
                 strand 
                   
                   
               
               
                 19 
               
               
                   
               
            
           
         
       
     
     wherein, capital letters C, U, and A indicated the base composition of the nucleotides; the lowercase m indicated that the nucleotide adjacent to the left side of the letter m was a methoxy modified nucleotide; the lowercase f indicated that the nucleotide adjacent to the left side of the letter f was a fluoro modified nucleotide; and the lowercase letter s indicated that the two nucleotides adjacent to the left and right of the letter s were linked by phosphorothioate. 
     In the preparation process of the sequences above, when the target sequence contained an unmodified nucleotide, under the conditions of cleavage and deprotection, after aqueous ammonia treatment, 0.4 ml/μmol N-methyl pyrrolidone was used to dissolve the product, and then 0.3 ml/μmol triethylamine and 0.6 ml/μmol triethylamine trihydrofluoride were added to remove 2′-TBDMS protection on ribose, with respect to the amount of the single-stranded nucleic acid. 
     After the siRNA or siRNA conjugate above was prepared, the siRNA or siRNA conjugate was freeze-dried into solid powder for later use. When in use, for example, water for injection, normal saline (NS), phosphate buffer (PB) or phosphate buffer solution (PBS) could be used to redissolve the siRNA or siRNA conjugate into a solution with the required concentration for use. 
     Experimental Example 1 
     In Vitro Inhibitory Activity of the siRNA of the Present Disclosure 
     HEK293A cells (purchased from Nanjing COBIOER Biotechnology Co., Ltd.) were cultured in H-DMEM complete media (HyClone company) containing 10% fetal bovine serum (FBS, Hyclone company) and 0.2 v % Penicillin-Streptomycin (Gibco, Invitrogen company) at 37° C. in an incubator containing 5% CO 2 /95% air. 
     According to the methods disclosed in Functional dissection of siRNA sequence by systematic DNA substitution: modified siRNA with a DNA seed arm is a powerful tool for mammalian gene silencing with significantly reduced off-target effect. Nucleic Acids Research, 2008.36(7), 2136-2151 written by Kumico Ui-Tei et.al., detection plasmids were constructed, and the to-be-evaluated siRNAs (siXOa0, siXOe0, siXOf0 and CON-siXOf) were transfected into HEK293A cells, and the inhibitory activity of siRNA was reflected by the expression level of double luciferase reporter gene. The specific steps were as follows: 
     [1] Construction of Detection Plasmids 
     Detection plasmids were constructed using psiCHECK™-2(Promega™) plasmid. The plasmid comprised one target sequence, i.e., the target sequence of the siRNA. For the to-be-evaluated siRNAs, the target sequences were respectively as shown below: 
     The target sequence of the siXOa0 was: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 731) 
               
               
                   
                 GAGATGAAGTTCAAGAATA 
               
            
           
         
       
     
     The target sequence of the siXOe0 was: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 732) 
               
               
                   
                 ACATGGACAACTGCTATAA 
               
            
           
         
       
     
     The target sequence of the siXOf0 was: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 733) 
               
               
                   
                 TAGCAAGCTCTCAGTATCA 
               
            
           
         
       
     
     The target sequence of the CON-siXOf was: 
     
       
         
           
               
               
            
               
                   
                 (SEQ ID NO: 734) 
               
               
                   
                 CTAGCAAGCTCTCAGTATC 
               
            
           
         
       
     
     The target sequence was cloned into the Xho I/Not I site of the psiCHECK™-2 plasmid. 
     [2] Transfection 
     HEK293A cells were seeded in a 96-well plate with 8×10 3  cells/well. After 16 hours, when the growth density of the cells reached 70-80%, the H-DMEM complete media in the culture wells were sucked up, and 80 μl of Opti-MEM media (GIBCO company) was added to each well to continue the culture for 1.5 hours. 
     For each siRNA, the corresponding detection plasmid was diluted into 200 ng/μl detection plasmid working solution with DEPC water. For each siRNA, siRNA and DEPC water were used to prepare siRNA working solutions with concentrations (calculated by siRNA) of 10 nM, 3 nM and 1 nM respectively. 
     For each siRNA, a 1A1 solution was prepared, and each part of the 1A1 solution contained 1 μl of siRNA working solution with a concentration of 10 nM, 0.05 μl of detection plasmid working solution (containing 10 ng of detection plasmids) and 10 μl of Opti-MEM media. 
     For each siRNA, a 1A2 solution was prepared, and each part of the 1A2 solution contained 1 μl of siRNA working solution with a concentration of 3 nM, 0.05 μl of detection plasmid working solution (containing 10 ng of detection plasmids) and 10 μl of Opti-MEM media. 
     For each siRNA, a 1A3 solution was prepared, and each part of the 1A3 solution contained 1 μl of siRNA working solution with a concentration of 1 nM, 0.05 μl of detection plasmid working solution (containing 10 ng of detection plasmids) and 10 μl of Opti-MEM media. 
     A 1B solution was prepared, and each part of the 1B solution contained 0.2 μl of Lipofectamine™ 2000 and 10 μl of Opti-MEM media. 
     A 1C solution was prepared, and each part of the 1C solution contained 0.05 μl of detection plasmid working solution (containing 10 ng of detection plasmids) and 10 μl of Opti-MEM media. 
     For each siRNA, one part of the 1B solution was mixed with one part of the 1A1 solution, one part of the 1A2 solution and one part of the 1A3 solution, and incubated for 20 minutes at room temperature to obtain transfection complexes 1X1, 1X2 and 1X3 respectively. One part of the 1B solution was mixed with one part of the 1C solution and incubated for 20 minutes at room temperature to obtain a transfection complex 1X4. 
     For each siRNA, the transfection complex 1X1 was respectively added into three culture wells, and evenly mixed, with an addition amount of 20 μl/well, to obtain a co-transfection mixture containing the siRNA with the final concentration of the siRNA about 0.1 nM, which was designated as test group 1. 
     For each siRNA, the transfection complex 1X2 was respectively added into another three culture wells, and evenly mixed, with an addition amount of 20 μl/well, to obtain a co-transfection mixture containing the siRNA with the final concentration of the siRNA about 0.03 nM, which was designated as test group 2. 
     For each siRNA, the transfection complex 1X3 was respectively added into another three culture wells, and evenly mixed, with an addition amount of 20 μl/well, to obtain a co-transfection mixture containing the siRNA with the final concentration of the siRNA about 0.01 nM, which was designated as test group 3. 
     The transfection complex 1X4 was respectively added into another three culture wells, and evenly mixed, with an addition amount of 20 μl/well, to obtain a co-transfection mixture not containing the siRNA, which was designated as a control group. 
     The co-transfection mixture containing the siRNA and the transfection mixture not containing the siRNA were co-transfected in culture wells for 4 hours, and then 100 μl of H-DMEM complete media containing 20% FBS was added to each well. The 96-well plate was placed in a CO 2  incubator to continuously culture for 24 hours. 
     [3] Detection 
     The media in the culture wells were sucked off, and 150 μl of a mixed solution of Dual-Gb® Luciferase and H-DMEM complete media (volume ratio 1:1) was added to each well, thoroughly mixed, and incubated at room temperature for 10 minutes, then 120 μl of the mixed solution was transferred to a 96-well enzyme-labeled plate, and a Firefly chemiluminescence value (Fir) was read by using Synergy II multifunctional microplate reader (BioTek company); then, 60 μl of Dual-Glo® Stop &amp; Gb® was added to each well, thoroughly mixed, incubated at room temperature for 10 minutes, then a  Renilla  chemiluminescence value (Ren) was read with a microplate reader according to the arrangement of reading the Fir. 
     The luminous ratio (Ratio=Ren/Fir) of each well was calculated, and the luminous Ratio (test) or Ratio (control) of each test group or control group was the average value of the Ratio of three culture wells; on the basis of the luminous ratio of the control group, the luminous ratio of each test group was normalized to obtain the ratio R of the Ratio (test)/Ratio (control), which was used to express the expression level of  Renilla  reporter gene, i.e., the residual activity. Inhibition percentage to the target sequence=(1−R)×100%. 
     The inhibitory activities of to-be-evaluated siRNA with different concentrations on the target sequence were shown in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Inhibition percentage on target sequence 
               
            
           
           
               
               
               
            
               
                   
                   
                 Inhibition percentage to target sequence (%) 
               
            
           
           
               
               
               
               
               
            
               
                 Preparation Example No. 
                 No. 
                 0.1 nM 
                 0.03 nM 
                 0.01 nM 
               
               
                   
               
               
                 Preparation Example 16 
                 siXOa0 
                 61.39 
                 43.69 
                 22.74 
               
               
                 Preparation Example 17 
                 siXOe0 
                 68.41 
                 46.94 
                 17.04 
               
               
                 Preparation Example 18 
                 siXOf0 
                 85.43 
                 68.79 
                 38.69 
               
               
                 Comparison Preparation  
                 CON-siXOf 
                 48.24 
                 24.86 
                 13.61 
               
               
                 Example 19 
               
               
                   
               
            
           
         
       
     
     The results show that the siRNA disclosed in the present disclosure has good inhibitory activity on the target sequences in vitro at all concentrations, and show a concentration dependence. Especially, the inhibition percentage to the target sequence is at least 61.39% when the concentration of the siRNA is 0.1 nM. Particularly, the siXOf shows 68.79% inhibition percentage to the target sequence at the concentration of 0.03 nM, and the inhibition percentage to the target sequence at the concentration of 0.1 nM is as high as 85.43%. In sharp contrast, although the sequence is very similar to the siXOf, in comparison to that the siRNA CON-siXOf only shows a inhibition percentage to the target sequence of 48.24% at the concentration of 0.1 nM, it is indicated that the siRNA of the present disclosure unexpectedly shows a good effect of inhibiting the expression of XO genes. 
     Experimental Example 2 
     IC 50  Detection of XO mRNA by siRNA in CAL-27 Cells 
     CAL-27 cells (purchased from Nanjing COBIOER Biotechnology Co., Ltd.) were cultured in H-DMEM complete media (HyClone company) containing 10% fetal bovine serum (FBS, Hyclone company) and 0.2 v % Penicillin-Streptomycin (Gibco, Invitrogen company) at 37° C. in an incubator containing 5% CO 2 /95% air. 
     CAL-27 cells were seeded in a 24-well plate with 7.5×10 4  cells/well. After 16 hours, when the growth density of the cells reached 70-80%, the H-DMEM complete media in the culture wells were sucked up, and 500 μl of Opti-MEM medium (GIBCO company) was added to each well to continue the culture for 1.5 hours. After washing with an HBSS solution, the cells were mixed evenly, and then seeded in a 96-well plate with 6×10 5  cells/well and an inoculation solution volume of 45 μl/well. 
     DEPC water was used to prepare each of the following siRNAs into eight siRNA working solutions with different concentrations comprising 20 μM, 4 μM, 0.8 μM, 0.16 μM, 0.032 μM, 0.0064 μM, 1.44 nM and 0.72 nM (calculated by siRNA). The used siRNAS were siXOa1M1S, siXOb1M1S, siXOc1M1S, siXOd1M1S, siXOe1M1S, and siXOf1M1S respectively. 
     The eight siRNA working solutions with different concentrations above were added into the above different culture wells seeded with CAL-27 cells at a volume of 15 μL/well. In this way, for each siRNA mentioned above, the final concentration of the siRNA in each culture well was 5 μM, 1 μM, 0.2 μM, 0.04 μM, 0.008 μM, 0.0016 μM, 0.32 nM, and 0.064 nM in turn, which were uniformly mixed and recorded as test groups. The culture wells seeded only with CAL-27 cells and not added with the siRNA working solution were taken as the control group. 
     An electrotransfer instrument (produced by EBXP-H1, Etta Cell Electrotransfer Instrument) was used for performing electrotransfection on the test groups and the control group. The transfection parameters were as follows: Voltage of 210 V; Pulse Duration of 100 μs; Pulse Number of 6 times; and Pulse Interval of 1000 ms. 
     240 μl of H-DMEM complete media containing 20% FBS was added to each culture well of the transfected test group and control group samples to obtain transfected cell culture solution. For each culture well, the transfected cell culture solution was transferred to two culture wells of a 24-well plate with 140 μl of cell culture solution per well, and then 855 μl of H-DMEM complete media containing 20% FBS was added to each culture well of the 24-well plate, and the culture was continued for 24 hours to obtain a to-be-tested cell culture solution. Then, RNAVzol (purchased from Vigorous Biotechnology Beijing Co., Ltd., article number N002) was used to respectively extract the total RNA from each well of the to-be-tested cell culture solution according to the steps described in the instructions. 
     For the cells in each well of the 24-well plate, 1 μg of the total RNA was taken, and the reagent provided by the reverse transcription kit Goldenstar™ RT6 cDNA Synthesis Kit (purchased from Beijing Tsingke Biotechnology Co., Ltd., article number TSK301M) was used, wherein Goldenstar™ Oligo (dT) 17  was selected as the primer, and 20 μl of reverse transcription reaction system was configured according to the reverse transcription operation steps in the kit manual to reverse the total RNA of the cells. The conditions for reverse transcription were as follows: the reverse transcription reaction system was incubated at 50° C. for 50 minutes, then incubated at 85° C. for 5 minutes, and finally incubated at 4° C. for 30 seconds. After the reaction, 80 μl of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. 
     For each reverse transcription reaction system, 5 μl of the solution containing cDNA was taken as the template, and 20 μl of qPCR reaction system was prepared by using the reagent provided by NovoStart® SYBR qPCR SuperMix Plus (purchased from Novoprotein Science and Technology Co., Ltd., article No. E096-01B), wherein the PCR primer sequences for amplifying the target gene XO and internal reference gene GAPDH were shown in Table 7, and the final concentration of each primer was 0.25 μM. Each qPCR reaction system was placed on ABI StepOnePlus Real-Time PCR instrument, and amplified by three-step method. The amplification procedure was pre-denatured at 95° C. for 10 minutes, then denatured at 95° C. for 30 seconds, annealed at 60° C. for 30 seconds, and extended at 72° C. for 30 seconds. After repeating the above denaturation, annealing and extension processes for 40 times, the product W containing amplified target gene XO and internal reference gene GAPDH was obtained. The product W was incubated at 95° C. for 1 minute, 55° C. for 30 seconds and 95° C. for 30 seconds in turn. The dissolution curves of the target gene XO and the internal reference gene GAPDH in the product W were collected by real-time fluorescence quantitative PCR, and the Ct values of the target gene XO and the internal reference gene GAPDH were obtained. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Sequences of Detection Primers 
               
            
           
           
               
               
               
            
               
                   
                 Upstream primer  
                 Downstream primer  
               
               
                 Gene 
                 (5′-3′ direction) 
                 (5′-3′ direction) 
               
               
                   
               
               
                 Human 
                 GACCCGACGGTATCTCCTTT 
                 ACGCCACAGACTTGACTTGC 
               
               
                 XO 
                 (SEQ ID NO: 735) 
                 (SEQ ID NO: 736) 
               
               
                   
               
               
                 Human 
                 GGTCGGAGTCAACGGATTT 
                 CCAGCATCGCCCCACTTGA 
               
               
                 GAPDH 
                 (SEQ ID NO: 737) 
                 (SEQ ID NO: 738) 
               
               
                   
               
            
           
         
       
     
     Comparative Ct(ΔΔCt) method was used to calculate relative quantitative expression of the target gene XO in each test group and the control group. The calculation method was as follows: 
       ΔCt(test group)=Ct(target gene of test group)−Ct(internal reference gene of test group)
 
       ΔCt(control group)=Ct(target gene of control group)−Ct(internal reference gene of control group)
 
       ΔΔCt(test group)=ΔCt(test group)−ΔCt(mean value of control group)
 
       ΔΔCt(control group)=ΔCt(control group)−ΔCt(mean value of control group)
 
     wherein, ΔCt(mean value of control group) was the arithmetic mean value of ΔCt(control group) of each of the two ulture wells of the control group. Therefore, each culture well of the test group and the control group corresponded to one ΔΔCt value. 
     On the basis of the control group, the expression level of XO mRNA in the test group was normalized, and the expression level of XO mRNA in the control group was defined as 100%. 
     The relative expression level of XO mRNA in the test group=2 −ΔΔCt(test group) ×100%. 
     For the siRNAs of the same test group, the mean value of the relative expression level of the XO mRNA of the test group at each concentration was the arithmetic mean value of the relative expression level of two culture wells at the concentration. 
     The log(inhibitor) vs. response—Variable slope of Graphpad 6.0 software was used to fit the dose-effect curve, and the IC50 value of each siRNA to XO mRNA was calculated according to the dose-effect curve. Specifically, the dose-response curve obtained by fitting conformed to the following calculation formula: 
     
       
         
           
             Y 
             = 
             
               Bot 
               + 
               
                 
                   Top 
                   - 
                   Bot 
                 
                 
                   1 
                   + 
                   
                     10 
                     
                       
                         ( 
                         
                           
                             X 
                             ′ 
                           
                           - 
                           X 
                         
                         ) 
                       
                       × 
                       HillSlope 
                     
                   
                 
               
             
           
         
       
     
     wherein: 
     Y is the relative expression level of mRNA of each test group, 
     X is the logarithmic value of the concentration of the siRNA used corresponding to the test group, 
     Bot is the Y value at the bottom of the steady stage, 
     Top is the Y value at the top of the steady stage, and 
     X′ is the X value at which Y is median value between the bottom and the top of the asymptote, and HillSlope is the slope of the curve obtained by fitting at X′. 
       FIGS. 1A-1F  are fitted dose-effect curve of the relative expression levels of XO mRNA in CAL-27 cells in vitro after transfection of siXOa1M1S, siXOb1M1S, siXOc1M1S, siXOd1M1S, siXOe1M1S and siXOf1M1S. According to the dose-effect curve and the corresponding calculation formula, the corresponding X 50  value when Y=50% was determined, and the IC 50  value of each siRNA was calculated to be 10{circumflex over ( )}X50 (nM). 
     The IC 50  value to XO mRNA of each siRNA is summarized in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 IC 50  of siRNA against XO mRNA 
               
            
           
           
               
               
               
               
            
               
                   
                 Preparation Example No. 
                 siRNA 
                 IC 50   
               
               
                   
                   
               
               
                   
                 Preparation Example 4 
                 siXOa1M1S 
                 0.1115 μM 
               
               
                   
                 Preparation Example 5 
                 siXOb1M1S 
                 0.8012 μM 
               
               
                   
                 Preparation Example 6 
                 siXOc1M1S 
                 0.3277 μM 
               
               
                   
                 Preparation Example 7 
                 siXOd1M1S 
                 0.0805 μM 
               
               
                   
                 Preparation Example 8 
                 siXOe1M1S 
                 0.0370 μM 
               
               
                   
                 Preparation Example 9 
                 siXOf1M1S 
                 0.0375 μM 
               
               
                   
                   
               
            
           
         
       
     
     It can be seen from Table 7 that the siRNA provided by the present disclosure exhibits higher inhibitory activity against XO mRNA in CAL-27 cells in vitro, and the IC 50  is between 0.037 μM and 0.3277 μM. 
     Experimental Example 3 
     Determination of Inhibition Percentage of siRNA to XO mRNA in Primary Hepatocytes of Mice 
     Primary hepatocytes of mice were extracted from fresh liver tissues of normal C57BL/6N mice, seeded into tissue culture dishes coated with type I collagen, and cultured in RPMI 1460 media containing 1×double-antibody and 10% FBS at 37° C., and cultured in an incubator containing 5% CO 2 /95% air for 30 minutes. 
     The culture media were discarded, and the density of the primary hepatocytes of mice was adjusted to 1×10 6  cells/mL by opti-MEM, to obtain the suspension of the primary hepatocytes of mice. Then, the suspension of the primary hepatocytes of mice obtained was added into different culture wells of a 24-well plate, and the primary hepatocytes of mice were seeded into the culture wells. The volume of the added suspension of the primary hepatocytes of mice was 0.5 mL/well, and the number of the primary hepatocytes of mice was 5×10 4  cells/well. 
     DEPC water was used to prepare each siRNA in the following siRNAs into 20 μM siRNA working solution, and the siRNA used was respectively siXOg1M1S, siXOh1M1S, siXOi1M1S, siXOj1M1S, siXOk1M1S or siXOl1M1S 
     A 1A solution was prepared. For each siRNA, the 1A solution was prepared respectively, and each part of the 1A solution contained 0.6 μl of the siRNA working solution above and 50 μl of Opti-MEM media in turn. 
     A 1B solution was prepared, and each part of the 1B solution contained 1 μl of Lipofectamine™ 2000 and 50 μl of Opti-MEM media. 
     One part of the 1B solution was respectively mixed with one part of the 1A solution of each siRNA obtained, and incubated at room temperature for 20 minutes to obtain a transfection complex 1X of each siRNA. 
     One part of the 1B solution was mixed with 50 μl of Opti-MEM media and incubated at room temperature for 20 minutes to obtain a transfection complex 1X′. 
     The transfection complex 1X of each siRNA was respectively added in the culture well, and evenly mixed, with an addition amount of 100 μl/well, to obtain a transfection complex containing the siRNA with the final concentration of the siRNA about 20 nM. The transfection complex 1X of each siRNA was respectively transfected with three culture wells to obtain a transfection mixture containing the siRNA, which was designated as the test group. 
     The transfection complex 1X′ was respectively added into another three culture wells with an addition amount of 100 μl/well, to obtain a transfection mixture not containing the siRNA, which was designated as a blank control group. 
     Each transfection mixture containing the siRNA and the transfection mixture not containing the siRNA were respectively transfected in different culture wells for 4 hours, and then 1 ml of H-DMEM complete media containing 20% FBS was added to each well. The 24-well plate was placed in a CO2 incubator to continuously culture at 37° C. for 24 hours. 
     Then, RNAVzol (purchased from Vigorous Biotechnology Beijing Co., Ltd., article number N002) was used to respectively extract the total RNA from the cells in each well according to the methods described in the instructions. 
     For the cells in each well, 1 μg of the total RNA was taken, and a reagent provided by a reverse transcription kit Goldenstar™ RT6 cDNA Synthesis Kit (purchased from Beijing Tsingke Biotechnology Co., Ltd., article number TSK301M) was used, wherein Goldenstar™ Oligo (dT) 17  was selected as the primer, and 20 μl of reverse transcription reaction system was configured according to the reverse transcription operation steps in the kit manual to reverse the total RNA of the cells in each well. The conditions for reverse transcription were as follows: for each reverse transcription reaction system, the reverse transcription reaction system was incubated at 50° C. for 50 minutes, then incubated at 85° C. for 5 minutes, and finally incubated at 4° C. for 30 seconds. After the reaction, 80 μl of DEPC water was added to the reverse transcription reaction system to obtain a solution containing cDNA. 
     For each reverse transcription reaction system, 5 μl of the solution containing cDNA was taken as the template, and 20 μl of qPCR reaction system was prepared by using the reagent provided by NovoStart® SYBR qPCR SuperMix Plus (purchased from Novoprotein Science and Technology Co., Ltd., article No. E096-01B), wherein the PCR primer sequences for amplifying the target gene XO and internal reference gene GAPDH were shown in Table 7, and the final concentration of each primer was 0.25 μM. Each qPCR reaction system was placed on ABI StepOnePlus Real-Time PCR instrument, and amplified by three-step method. The amplification procedure was pre-denatured at 95° C. for 10 minutes, then denatured at 95° C. for 30 seconds, annealed at 60° C. for 30 seconds, and extended at 72° C. for 30 seconds. After repeating the above denaturation, annealing and extension processes for 40 times, the product W containing amplified target gene XO and internal reference gene GAPDH was obtained. The product W was incubated at 95° C. for 15 seconds, 60° C. for 1 minute and 95° C. for 15 seconds in turn. The dissolution curves of the target gene XO and the internal reference gene GAPDH in the product W were collected by real-time fluorescence quantitative PCR, and the Ct values of the target gene XO and the internal reference gene GAPDH were obtained. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Primer information 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Nucleotide 
                 SEQ 
               
               
                 Name of gene 
                 Type of primer 
                 sequence (5′-3′) 
                 ID NO 
               
               
                   
               
               
                 Mouse XO 
                 Upstream primer 
                 AACAGAATTGTAGTCCGAGTGAA 
                 739 
               
               
                   
                 Downstream primer 
                 GTCTGCCACCAGTTATGAGC 
                 740 
               
               
                   
               
               
                 Mouse 
                 Upstream primer 
                 TGCACCACCAACTGCTTAG 
                 741 
               
               
                 GAPDH 
                 Downstream primer 
                 GGATGCAGGGATGATGTTC 
                 742 
               
               
                   
               
            
           
         
       
     
     Comparative Ct(ΔΔCt) method was used to calculate relative quantitative expression of the target gene XO in each test group. The calculation method was as follows: 
       ΔCt(test group)=Ct(target gene of test group)−Ct(internal reference gene of test group)
 
       ΔCt(control group)=Ct(target gene of control group)−Ct(internal reference gene of control group)
 
       ΔΔCt(test group)=ΔCt(test group)−ΔCt(mean value of control group)
 
       ΔΔCt(control group)=ΔCt(control group)−ΔCt(mean value of control group)
 
     wherein, ΔCt(mean value of control group) was the arithmetic mean value of ΔCt(control group) of each of the three ulture wells of the control group. Therefore, each culture well of the test group and the control group corresponded to one ΔΔCt value. 
     On the basis of the control group, the expression level of XO mRNA in the test group was normalized, and the expression level of XO mRNA in the blank control group was defined as 100%. 
     The relative expression level of XO mRNA in the test group=2 −ΔΔCt(test group) ×100% 
     The inhibition percentage to XO mRNA of the test group=(1−the relative expression level of XO mRNA of the test group)×100% 
       FIG. 2  is a histogram showing the relative expression level of XO mRNA in primary hepatocytes of mice after transfection of the siXOg1M1S, the siXOh1M1S, the siXOi1M1S, the siXOj1M1S, the siXOk1M1S and the siXOl1M1S of the present disclosure. Further, the inhibition percentage to XO mRNA of each siRNA is summarized in Table 9. For the siRNAs of the same test group, the inhibition percentage to the XO mRNA was the arithmetic mean value of the inhibition percentage of the test group to XO mRNA determined through the three culture wells. In  FIG. 2 , the siRNA7-12 was corresponding to siXOg1M1S, siXOh1M1S, siXOi1M1S, siXOj1M1S, siXOk1M1S and siXOl1M1S in sequence. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Inhibition to XO mRNA in primary hepatocytes of mice 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Inhibition percentage  
               
               
                   
                 Preparation Example 
                 No. 
                 to XO mRNA % 
               
               
                   
                   
               
               
                   
                 Preparation Example 10 
                 siXOg1M1S 
                 80.90 
               
               
                   
                 Preparation Example 11 
                 siXOh1M1S 
                 84.19 
               
               
                   
                 Preparation Example 12 
                 siXOi1M1S 
                 88.07 
               
               
                   
                 Preparation Example 13 
                 siXOj1M1S 
                 86.92 
               
               
                   
                 Preparation Example 14 
                 siXOk1M1S 
                 78.95 
               
               
                   
                 Preparation Example 15 
                 siXOl1M1S 
                 81.25 
               
               
                   
                   
               
            
           
         
       
     
     It can be seen from the results in Table 9 that the siRNA provided by the present disclosure shows high inhibitory activity to XO mRNA in primary hepatocytes of mice, and the inhibition percentage to XO mRNA is at least 78.95%, even as high as 88.07% under the siRNA concentration of 20 nM. 
     Experimental Example 4 
     Expression Inhibition of XO mRNA by siRNA Conjugate in Mice 
     C57BL/6N mice were randomly divided into groups (all females) with five mice in each group and respectively numbered. In the way of subcutaneous injection, siRNA conjugates L10-siXOi1M1S and L10-siXOk1M1S and comparison siRNA conjugate NC were given to each group of mice at a dose of 3 mg/kg (calculated by siRNA). The siRNA conjugates were provided in the form of 0.9% sodium chloride aqueous solution containing 0.6 mg/ml siRNA conjugate (calculated by siRNA), and the administration volume was 5 ml/kg. 
     One group of mice was given 1× PBS with an administration volume of 5 ml/kg, and served as the blank control group. 
     The animals were sacrificed on the 7 th  day after administration, and liver tissues of each mouse were collected and stored with RNA later (Sigma Aldrich company). The liver tissues were homogenized with a tissue homogenizer, and then extracted with Trizol (Thermo Fisher company) according to the operation steps described in the manual to obtain the total RNA. 
     According to the method of the Experimental Example 3, the expression level and inhibition percentage to XO mRNA were detected by fluorescence quantitative PCR. The only difference was that the extracted total RNA was reversely transcribed into cDNA by using ImProm-IITM reverse transcription kit (Promega company) according to the instructions thereof to obtain a solution containing cDNA, and then the expression level of XO mRNA in the liver tissues was detected by fluorescence quantitative PCR kit (Beijing CoWin Biosciences). In this fluorescence quantitative PCR method, mouse GAPDH(mGAPDH) genes were used as internal reference genes, and XO and mouse GAPDH were detected by using primers for XO and mouse GAPDH respectively. The sequences of the detection primers were shown in Table 8. The expression level of XO mRNA in the blank control group was recorded as 100%, and accordingly, the inhibition percentage to XO mRNA expression level was recorded as 0%. The test results of the test group of the siRNA conjugate were normalized by the expression level of XO mRNA in the control group, and the results were shown in  FIG. 3  and Table 10. In  FIG. 3 , conjugate 1 refers to L10-siXOi1M1S, and conjugate 2 refers to L10-siXOk1M1S. 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Inhibition percentages to XO mRNA by  
               
               
                 siRNA conjugates of different concentrations 
               
            
           
           
               
               
               
            
               
                   
                   
                 Inhibition percentage  
               
               
                 Preparation Example No. 
                 siRNA conjugate 
                 to XO mRNA (%) 
               
               
                   
               
               
                 Preparation Example 1 
                 L10-siXOi1M1S 
                 70.9 
               
               
                 Preparation Example 2 
                 L10-siXOk1M1S 
                 76.2 
               
               
                 Comparison Preparation  
                 NC 
                 10.0 
               
               
                 Example 3 
               
               
                   
               
            
           
         
       
     
     It can be seen from the results in Table 10 that the siRNA conjugate provided by the present disclosure shows an inhibition rate of at least 70.9% and even as high as 76.2% to XO mRNA under the siRNA concentration of 3 mg/kg, and shows an excellent inhibition effect to XO mRNA. 
     Some embodiments of the present disclosure are described in detail above, but the present disclosure is not limited to the specific details of the above-described embodiments. Various simple variations of the technical solution of the present disclosure can be made within the scope of the technical concept of the present disclosure, and these simple variations are within the scope of the present disclosure. 
     In addition, it is to be noted that each of the specific technical features described in the above embodiments can be combined in any suitable manner as long as no contradiction is caused. In order to avoid unnecessary repetition, the various possible combination manners are no longer described in the present disclosure. 
     In addition, the various different embodiments of the present disclosure may also be carried out in any combination as long as it does not contravene the idea of the present disclosure, which should also be regarded as the disclosure of the present disclosure.