A double-stranded nucleic acid agent comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: the first nucleic acid strand comprises (i) a first RNA region with at least 2 consecutive RNA nucleotides that can be recognized by RNase H when the first nucleic acid strand is hybridized to the second nucleic acid strand, (ii) a therapeutic oligonucleotide region wherein at least one internucleotide linkage at the 3' and at the 5' end of the therapeutic oligonucleotide region is more nuclease-resistant than a natural internucleotide linkage, and (iii) at least one internucleotide linkage at the 3' and at the 5' end of the first nucleic acid strand is more nuclease-resistant than a natural internucleotide linkage; the second nucleic acid strand comprises (i) a first DNA region that is hybridized to the first RNA region of the first nucleic acid strand and can promote the recognition of the at least 2 consecutive RNA nucleotides in the first nucleic acid strand by RNase H, and (ii) at least one internucleotide linkage at the 3' and at the 5' end of the second nucleic acid strand is more nuclease-resistant than a natural internucleotide linkage; and the therapeutic oligonucleotide region of the first nucleic acid strand is not capable of hybridization with the second nucleic acid strand and the double-stranded nucleic acid agent further comprises a targeting moiety which is selected from a lipid, a sugar, a peptide, and a protein and joined to the 3'-terminal nucleotide or the 5'-terminal nucleotide of the second nucleic acid strand, or to the 3'-terminal nucleotide or the 5'-terminal nucleotide of the first nucleic acid strand.. the first nucleic acid strand comprises (i) a first RNA region with at least 2 consecutive RNA nucleotides that can be recognized by RNase H when the first nucleic acid strand is hybridized to the second nucleic acid strand, (ii) a therapeutic oligonucleotide region wherein at least one internucleotide linkage at the 3' and at the 5' end of the therapeutic oligonucleotide region is more nuclease-resistant than a natural internucleotide linkage, and (iii) at least one internucleotide linkage at the 3' and at the 5' end of the first nucleic acid strand is more nuclease-resistant than a natural internucleotide linkage; the second nucleic acid strand comprises (i) a first DNA region that is hybridized to the first RNA region of the first nucleic acid strand and can promote the recognition of the at least 2 consecutive RNA nucleotides in the first nucleic acid strand by RNase H, and (ii) at least one internucleotide linkage at the 3' and at the 5' end of the second nucleic acid strand is more nuclease-resistant than a natural internucleotide linkage; and the therapeutic oligonucleotide region of the first nucleic acid strand is not capable of hybridization with the second nucleic acid strand and the double-stranded nucleic acid agent further comprises a targeting moiety which is selected from a lipid, a sugar, a peptide, and a protein and joined to the 3'-terminal nucleotide or the 5'-terminal nucleotide of the second nucleic acid strand, or to the 3'-terminal nucleotide or the 5'-terminal nucleotide of the first nucleic acid strand..