sinusoidal endothelial cells (LSECs) and the KCs. Hydrophobic NCs are likewise more quickly captured by these cells [303]. On the other hand, smaller NCs can reach the space of Disse through the LSEC fenestrations and thus the HSC and the hepatocytes, especially if they have been decorated with poly-ethylene glycol (PEG) to improve their stealthiness and escape the immune surveillance [303,304]. However, this passive targeting is not sufficiently precise to target one liver cell type and targeting a moiety is recommended for that purpose, as previously reviewed [291,292] and summarized here in Figure 7.

### 8.3. Therapeutic Approaches Targeting miRNAs in Clinical Trials and Future Perspectives

To date, no miRNA suppression or replacement strategy using an active targeted delivery system exists in the therapeutic arsenal despite the promise of success. MiRNA-based clinical trials, investigational miRNA-based therapies, patented, approved, or marketed medicine have been reviewed [279,282,305,306]. Although there are currently no clinical trials on miRNAs targeting in ALD, some miRNAs involved in ALD or ALD-related HCC have been studied in other contexts (see examples in Table 3). Few clinical trials have been devoted to HCC or Hepatitis C virus (HCV), such as miravirsen (anti-miR-122), MRX34, or RG-101 (anti-miR-122), which have not yet passed clinical trial phase I/II [307–309]. MRX34 has even been halted because of off-target delivery of the miRNA mimic [310]. However, very sparse data are published on miRNA as a clinical target to treat the consecutive ALD stages before the occurrence of HCC.

<table><caption>**Table 3.** Examples of miRNA-based clinical trials which are deregulated in ALD or ALD-related HCC (clinicaltrials.gov, retrieved in 25 October 2023).</caption><thead><tr><td>Identification</td><td>Title</td><td>Phase</td><td>miRNA Target</td><td>Disease</td></tr></thead><tbody><tr><td>NCT01727934</td><td>Miravirsen Study in Null Responder to Pegylated Interferon Alpha Plus Ribavirin Subjects with Chronic Hepatitis C</td><td>II</td><td>miR-122</td><td>Hepatitis C virus infection</td></tr><tr><td>NCT02862145</td><td>Pharmacodynamics Study of MRX34, MicroRNA Liposomal Injection in Melanoma Patients with Biopsy Accessible Lesions (MRX34-102)</td><td>I</td><td>miR-34</td><td>Advanced melanoma</td></tr><tr><td>NCT03373786</td><td>A Study of RG-012 in Subjects with Alport Syndrome</td><td>I</td><td>miR-21</td><td>Alport syndrome</td></tr><tr><td>NCT02369198</td><td>MesomiR 1: A Phase I Study of TargomiRs as 2nd or 3rd Line Treatment for Patients with Recurrent MPM and NSCLC</td><td>I</td><td>miR-16</td><td>Malignant Pleural Mesothelioma (MPM) and Advanced Non-Small Cell Lung Cancer (NSCLC)</td></tr><tr><td>NCT03601052</td><td>Efficacy, Safety, and Tolerability of Remlarsen (MRG-201) Following Intradermal Injection in Subjects with a History of Keloids</td><td>II</td><td>miR-29</td><td>Keloid formation</td></tr><tr><td>NCT03837457</td><td>PRISM: Efficacy and Safety of Cobomarsen (MRG-106) in Subjects with Mycosis Fungoides Who Have Completed the SOLAR Study (PRISM)</td><td>II</td><td>miR-155</td><td>Cutaneous T-Cell Lymphoma (CTCL) and Mycosis Fungoides (MF)</td></tr><tr><td>NCT0280552</td><td>Safety, Tolerability and Pharmacokinetics of MRG-106 in Patients with Mycosis Fungoides (MF), CLL, DLBCL or ATLL</td><td>I</td><td>miR-155</td><td>Cutaneous T-Cell Lymphoma (CTCL), Mycosis Fungoides (MF), Chronic Lymphocytic Leukemia (CLL), Diffuse Large B-Cell Lymphoma (DLBCL) and Adult T-Cell Leukemia/Lymphoma (ATLL)</td></tr><tr><td>NCT03713320</td><td>SOLAR: Efficacy and Safety of Cobomarsen (MRG-106) vs. Active Comparator in Subjects with Mycosis Fungoides (SOLAR)</td><td>II</td><td>miR-155</td><td>Cutaneous T-Cell Lymphoma (CTCL) and Mycosis Fungoides (MF)</td></tr><tr><td>NCT03603431</td><td>Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MRG-110 Following Intradermal Injection in Healthy Volunteers</td><td>I</td><td>miR-92a</td><td>Ischemia</td></tr></tbody></table>
Some carriers have been developed, encouraging further research. For example, a miR-122 lipoplex consisting of a cationic lipid nanoparticle formulation allowed miR-122 hepatic delivery and restored deregulated gene expression in the HCC mouse model [311]. Other lipid-based or polymeric nanocarriers for hepatic miR-122 delivery demonstrated a hepatic tropism but without actively targeting a specific cell type [297,312]. Adding a targeting moiety ameliorates the efficacy of the miRNA delivery, like the use of GE11 (targeting the EGF Receptor overexpressed in HCC) decorated Virus-like Particle for sponging miR-21 together with the delivery of a miR-122 mimic [285]. Other have described a galactosylated-chitosan NC to deliver miR-122 that sensitized HCC cells to a co-delivered anticancer drug [313]. In a context of steatosis and HCC, exosomes genetically modified to express anti-miR-199a-5p or miR-223 [314,315], lactosylated-polymeric methacrylate-based NC loaded with miR-146b mimic [316], or anti-glypican3-decorated liposome loaded with an anticancer and anti-miR-27a [317] are other examples of hepatocyte-targeted miRNA delivery systems. Besides those, the use of small molecules could be of interest as shown in a mouse model of ALD in which Baicalin-stimulated expression of miR-205 led to the inhibition of NF-kB-driven inflammation and finally protected the liver against ethanol-induced injury [88]. This latter strategy could be enhanced by the use of hepatic-targeted carriers and assessed for its ability to limit HCC occurrence. Focusing on HSC reveals that the main targeting strategy exploits the affinity of these cells for the retinol binding protein with liposome loaded with vitamin A and miRNA [318,319], and a clinical trial to deliver oligonucleotides to HSC using Vitamin A (NCT02227459). Finally, passive targeting is used for miRNA delivery in KCs, as described by Liu et al. in mice [320], where a polymeric carrier with a diameter of 279 nm and a positive charge serves as a synthetic anti-NFkB miRNA delivery platform. However, one can fear off-target side effects as for MRX34 [302]. More recently, NCs have been developed to target both KCs and HSCs and disrupt their detrimental crosstalk in ALD, especially to reverse liver fibrosis. The two reported strategies relied on polymeric NCs able to deliver anti-miR-155 to KCs in parallel with the blockade of the HSC's CXCR4. Cyclam derivatives, known to inhibit CXCR4 [321], decorated polyethylene imine core NCs loaded with anti-miR-155. With sizes of 60 and 150 nm, respectively, and a positive surface charge, both NCs reversed the hepatic damages in an ethanol/CCl4 mouse model of liver fibrosis [322,323]. Finally, starting from an amino-lipid-based nanocarrier library, it has been demonstrated that the surface of the nanocarriers can be functionalized by blood circulating proteins to obtain an active targeting of the liver cells. Depending on the amino-lipid, NCs were decorated by a corona of either apolipoprotein E or albumin, leading to the targeting of the hepatocytes or KCs, respectively [324], while sharing similar physical properties. These carriers have proven efficient in the delivery of let-7 g miRNA in an aggressive myc-driven HCC mouse model.

## 9. Conclusions

Although ALD is the most prevalent liver disease in developed countries, there are currently no reviews documenting the role of miRNAs in all the stages of this disease. Our study is not only providing an exhaustive overview of the role of miRNAs in the development of ALD but also provides evidence that deregulated miRNAs at each stage of the disease contribute to the establishment of a neoplastic phenotype. More than one hundred miRNAs are discussed, thus highlighting the importance of post-transcriptional regulation of gene expression in ALD and HCC and raising many questions regarding the therapeutic targeting of these miRNAs. Currently, they are no miRNA-targeted delivery systems for the treatment of ALD on the market. Although many strategies can be designed to efficiently target these miRNAs, it remains to be determined which ones should be targeted. Moreover, more suitable in vivo models are tremendously required to characterize the role of these miRNAs in ALD/HCC and evaluate the potential of their therapeutic potential. The very first stages of ALD, including steatosis, are not a primary source of research and the targeted delivery of miRNA mainly focuses on the later stages like fibrosis resolution or HCC remission. The development of dual therapeutics, combining
Some carriers have been developed, encouraging further research. For example, a miR-122 lipoplex consisting of a cationic lipid nanoparticle formulation allowed miR-122 hepatic delivery and restored deregulated gene expression in the HCC mouse model [311]. Other lipid-based or polymeric nanocarriers for hepatic miR-122 delivery demonstrated a hepatic tropism but without actively targeting a specific cell type [297,312]. Adding a targeting moiety ameliorates the efficacy of the miRNA delivery, like the use of GE11 (targeting the EGF Receptor overexpressed in HCC) decorated Virus-like Particle for sponging miR-21 together with the delivery of a miR-122 mimic [285]. Other have described a galactosylated-chitosan NC to deliver miR-122 that sensitized HCC cells to a co-delivered anticancer drug [313]. In a context of steatosis and HCC, exosomes genetically modified to express anti-miR-199a-5p or miR-223 [314,315], lactosylated-polymeric methacrylate-based NC loaded with miR-146b mimic [316], or anti-glypican3-decorated liposome loaded with an anticancer and anti-miR-27a [317] are other examples of hepatocyte-targeted miRNA delivery systems. Besides those, the use of small molecules could be of interest as shown in a mouse model of ALD in which Baicalin-stimulated expression of miR-205 led to the inhibition of NF-kB-driven inflammation and finally protected the liver against ethanol-induced injury [88]. This latter strategy could be enhanced by the use of hepatic-targeted carriers and assessed for its ability to limit HCC occurrence. Focusing on HSC reveals that the main targeting strategy exploits the affinity of these cells for the retinol binding protein with liposome loaded with vitamin A and miRNA [318,319], and a clinical trial to deliver oligonucleotides to HSC using Vitamin A (NCT02227459). Finally, passive targeting is used for miRNA delivery in KCs, as described by Liu et al. in mice [320], where a polymeric carrier with a diameter of 279 nm and a positive charge serves as a synthetic anti-NFkB miRNA delivery platform. However, one can fear off-target side effects as for MRX34 [302]. More recently, NCs have been developed to target both KCs and HSCs and disrupt their detrimental crosstalk in ALD, especially to reverse liver fibrosis. The two reported strategies relied on polymeric NCs able to deliver anti-miR-155 to KCs in parallel with the blockade of the HSC's CXCR4. Cyclam derivatives, known to inhibit CXCR4 [321], decorated polyethylene imine core NCs loaded with anti-miR-155. With sizes of 60 and 150 nm, respectively, and a positive surface charge, both NCs reversed the hepatic damages in an ethanol/CCl4 mouse model of liver fibrosis [322,323]. Finally, starting from an amino-lipid-based nanocarrier library, it has been demonstrated that the surface of the nanocarriers can be functionalized by blood circulating proteins to obtain an active targeting of the liver cells. Depending on the amino-lipid, NCs were decorated by a corona of either apolipoprotein E or albumin, leading to the targeting of the hepatocytes or KCs, respectively [324], while sharing similar physical properties. These carriers have proven efficient in the delivery of let-7 g miRNA in an aggressive myc-driven HCC mouse model.

## 9. Conclusions

Although ALD is the most prevalent liver disease in developed countries, there are currently no reviews documenting the role of miRNAs in all the stages of this disease. Our study is not only providing an exhaustive overview of the role of miRNAs in the development of ALD but also provides evidence that deregulated miRNAs at each stage of the disease contribute to the establishment of a neoplastic phenotype. More than one hundred miRNAs are discussed, thus highlighting the importance of post-transcriptional regulation of gene expression in ALD and HCC and raising many questions regarding the therapeutic targeting of these miRNAs. Currently, they are no miRNA-targeted delivery systems for the treatment of ALD on the market. Although many strategies can be designed to efficiently target these miRNAs, it remains to be determined which ones should be targeted. Moreover, more suitable in vivo models are tremendously required to characterize the role of these miRNAs in ALD/HCC and evaluate the potential of their therapeutic potential. The very first stages of ALD, including steatosis, are not a primary source of research and the targeted delivery of miRNA mainly focuses on the later stages like fibrosis resolution or HCC remission. The development of dual therapeutics, combining
several drugs (anti-miR and anticancer) or targeting several cell types (KCs and HSCs), together with a passive-to-active targeting, pave the way for efficient future treatments of ALD. Furthermore, increasing evidence challenges the dogmatic view of miRNAs as strict inhibitors of gene expression, and suggest, in contrast, that miRNAs can induce gene expression [325]. Finally, it should be remembered that miRNA-dependent regulation is a complex process tightly regulated by other trans-acting factors (e.g., lncRNAs or RBPs), which regulate the bioavailability and the activity of miRNAs. Emerging evidence indicates that this interplay is relevant in ALD, as shown by miR-214, which is sponged and inactivated by the ethanol-induced lncRNA urothelial cancer-associated 1 (UCA1) in a hepatocyte cell line [326]. The complexity of miRNA-dependent functions is further enhanced by miRNAs editing by specific enzymes (e.g., Adenosine Deaminase, RNA specific, ADAR) controlling miRNA functions and whose expression is often imbalanced in pathological states (i.e., HCC) [327,328].

**Author Contributions:** Conceptualization, N.L. and C.S.; writing—review and editing, M.J., R.C., S.K., N.L. and C.S.; supervision, C.S.; funding acquisition, C.S. and N.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the "Métropole Européenne de Lille" (MEL N°Convention_2021_ESR_11), le dispositif StaRs de la région Hauts-de-France (Arreté n° 22000953), la ligue contre le cancer (Septentrion), and the Agence Nationale pour la Recherche (ANR CPJ_Sobolewski).

**Conflicts of Interest:** The authors declare no conflict of interest.

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several drugs (anti-miR and anticancer) or targeting several cell types (KCs and HSCs), together with a passive-to-active targeting, pave the way for efficient future treatments of ALD. Furthermore, increasing evidence challenges the dogmatic view of miRNAs as strict inhibitors of gene expression, and suggest, in contrast, that miRNAs can induce gene expression [325]. Finally, it should be remembered that miRNA-dependent regulation is a complex process tightly regulated by other trans-acting factors (e.g., lncRNAs or RBPs), which regulate the bioavailability and the activity of miRNAs. Emerging evidence indicates that this interplay is relevant in ALD, as shown by miR-214, which is sponged and inactivated by the ethanol-induced lncRNA urothelial cancer-associated 1 (UCA1) in a hepatocyte cell line [326]. The complexity of miRNA-dependent functions is further enhanced by miRNAs editing by specific enzymes (e.g., Adenosine Deaminase, RNA specific, ADAR) controlling miRNA functions and whose expression is often imbalanced in pathological states (i.e., HCC) [327,328].

**Author Contributions:** Conceptualization, N.L. and C.S.; writing—review and editing, M.J., R.C., S.K., N.L. and C.S.; supervision, C.S.; funding acquisition, C.S. and N.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the "Métropole Européenne de Lille" (MEL N°Convention_2021_ESR_11), le dispositif StaRs de la région Hauts-de-France (Arreté n° 22000953), la ligue contre le cancer (Septentrion), and the Agence Nationale pour la Recherche (ANR CPJ_Sobolewski).

**Conflicts of Interest:** The authors declare no conflict of interest.

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108. Chen, D.; Yan, Y.; Wang, X.; Li, S.; Liu, Y.; Yu, D.; He, Y.; Deng, R.; Liu, Y.; Xu, M.; et al. Chronic Alcohol Exposure Promotes HCC Stemness and Metastasis through β-Catenin/MiR-22-3p/TET2 Axis. *Aging* **2021**, *13*, 14433–14455.
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117. Zaiou, M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. *Cells* **2023**, *12*, 1205. [CrossRef]

118. Chen, Y.; Patel, V.; Bang, S.; Cohen, N.; Millar, J.; Kim, S.F. Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3. *PLoS ONE* **2012**, *7*, e49906. [CrossRef]

119. Xiao, X.; Song, B.-L. SREBP: A Novel Therapeutic Target. *Acta Biochim. Biophys. Sin.* **2013**, *45*, 2–10. [CrossRef]

120. Zhu, L.; Liao, R.; Huang, J.; Yan, H.; Xiao, C.; Yang, Y.; Wang, H.; Yang, C. The MiR-216/MiR-217 Cluster Regulates Lipid Metabolism in Laying Hens With Fatty Liver Syndrome via PPAR/SREBP Signaling Pathway. *Front. Vet. Sci.* **2022**, *9*, 913841. [CrossRef]

121. Hu, M.; Wang, F.; Li, X.; Rogers, C.Q.; Liang, X.; Finck, B.N.; Mitra, M.S.; Zhang, R.; Mitchell, D.A.; You, M. Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice. *Hepatol. Baltim. Md* **2012**, *55*, 437–446. [CrossRef] [PubMed]

122. Harris, T.E.; Finck, B.N. Dual Function Lipin Proteins and Glycerolipid Metabolism. *Trends Endocrinol. Metab. TEM* **2011**, *22*, 226–233. [CrossRef] [PubMed]

123. Ponugoti, B.; Kim, D.-H.; Xiao, Z.; Smith, Z.; Miao, J.; Zang, M.; Wu, S.-Y.; Chiang, C.-M.; Veenstra, T.D.; Kemper, J.K. SIRT1 Deacetylates and Inhibits SREBP-1C Activity in Regulation of Hepatic Lipid Metabolism. *J. Biol. Chem.* **2010**, *285*, 33959–33970. [CrossRef] [PubMed]

124. Liu, F.; Zhu, X.; Jiang, X.; Li, S.; Lv, Y. Transcriptional Control by HNF-1: Emerging Evidence Showing Its Role in Lipid Metabolism and Lipid Metabolism Disorders. *Genes Dis.* **2022**, *9*, 1248–1257. [CrossRef] [PubMed]

125. Lawler, J.F.; Yin, M.; Diehl, A.M.; Roberts, E.; Chatterjee, S. Tumor Necrosis Factor-α Stimulates the Maturation of Sterol Regulatory Element Binding Protein-1 in Human Hepatocytes through the Action of Neutral Sphingomyelinase. *J. Biol. Chem.* **1998**, *273*, 5053–5059. [CrossRef] [PubMed]

126. Donohue, T.M.; Osna, N.A.; Trambly, C.S.; Whitaker, N.P.; Thomes, P.G.; Todero, S.L.; Davis, J.S. Early Growth Response-1 Contributes to Steatosis Development after Acute Ethanol Administration. *Alcohol. Clin. Exp. Res.* **2012**, *36*, 759–767. [CrossRef] [PubMed]

127. McMullen, M.R.; Pritchard, M.T.; Wang, Q.; Millward, C.A.; Croniger, C.M.; Nagy, L.E. Early Growth Response-1 Transcription Factor Is Essential for Ethanol-Induced Fatty Liver Injury in Mice. *Gastroenterology* **2005**, *128*, 2066–2076. [CrossRef]

128. Li, W.; Li, K.; Wang, Z.; Fa, Z. MicroRNA-377-3p Promotes Cell Proliferation and Inhibits Cell Cycle Arrest and Cell Apoptosis in Hepatocellular Carcinoma by Affecting EGR1-Mediated P53 Activation. *Pathol. Res. Pract.* **2022**, *234*, 153855. [CrossRef]

129. Osna, N.A.; Donohue, T.M.; Kharbanda, K.K. Alcoholic Liver Disease: Pathogenesis and Current Management. *Alcohol Res. Curr. Rev.* **2017**, *38*, 147–161.

130. Krammer, J.; Digel, M.; Ehehalt, F.; Stremmel, W.; Füllekrug, J.; Ehehalt, R. Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4 and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells. *Int. J. Med. Sci.* **2011**, *8*, 599–614. [CrossRef]

131. Lin, H.-Y.; Wang, F.-S.; Yang, Y.-L.; Huang, Y.-H. MicroRNA-29a Suppresses CD36 to Ameliorate High Fat Diet-Induced Steatohepatitis and Liver Fibrosis in Mice. *Cells* **2019**, *8*, 1298. [CrossRef]

132. Wang, X.; Ma, Y.; Yang, L.-Y.; Zhao, D. MicroRNA-20a-5p Ameliorates Non-Alcoholic Fatty Liver Disease via Inhibiting the Expression of CD36. *Front. Cell Dev. Biol.* **2020**, *8*, 596329. [CrossRef] [PubMed]

133. Ding, D.; Ye, G.; Lin, Y.; Lu, Y.; Zhang, H.; Zhang, X.; Hong, Z.; Huang, Q.; Chi, Y.; Chen, J.; et al. MicroRNA-26a-CD36 Signaling Pathway: Pivotal Role in Lipid Accumulation in Hepatocytes Induced by PM2.5 Liposoluble Extracts. *Environ. Pollut. Barking Essex* **1987** **2019**, *248*, 269–278. [CrossRef] [PubMed]

134. Schmoldt, A.; Benthe, H.F.; Haberland, G. Digitoxin Metabolism by Rat Liver Microsomes. *Biochem. Pharmacol.* **1975**, *24*, 1639–1641. [CrossRef] [PubMed]

135. Feng, X.; Wang, Z.; Fillmore, R.; Xi, Y. MiR-200, a New Star MiRNA in Human Cancer. *Cancer Lett.* **2014**, *344*, 166–173. [CrossRef]

136. Huang, Q.; Li, J.; Zheng, J.; Wei, A. The Carcinogenic Role of the Notch Signaling Pathway in the Development of Hepatocellular Carcinoma. *J. Cancer* **2019**, *10*, 1570–1579. [CrossRef] [PubMed]

137. Zheng, X.-B.; Chen, X.-B.; Xu, L.-L.; Zhang, M.; Feng, L.; Yi, P.-S.; Tang, J.-W.; Xu, M.-Q. MiR-203 Inhibits Augmented Proliferation and Metastasis of Hepatocellular Carcinoma Residual in the Promoted Regenerating Liver. *Cancer Sci.* **2017**, *108*, 338–346. [CrossRef]

138. Yang, F.; Hu, Y.; Liu, H.-X.; Wan, Y.-J.Y. MiR-22-Silenced Cyclin A Expression in Colon and Liver Cancer Cells Is Regulated by Bile Acid Receptor. *J. Biol. Chem.* **2015**, *290*, 6507–6515. [CrossRef]

139. Csak, T.; Ganz, M.; Pespisa, J.; Kodys, K.; Dolganiuc, A.; Szabo, G. Fatty Acid and Endotoxin Activate Inflammasomes in Mouse Hepatocytes That Release Danger Signals to Stimulate Immune Cells. *Hepatol. Baltim. Md* **2011**, *54*, 133–144. [CrossRef]

140. Glaser, T.; Baiocchi, L.; Zhou, T.; Francis, H.; Lenci, L.; Grassi, G.; Kennedy, L.; Liangpunsakul, S.; Glaser, S.; Alpini, G.; et al. Pro-Inflammatory Signalling and Gut-Liver Axis in Non-Alcoholic and Alcoholic Steatohepatitis: Differences and Similarities along the Path. *J. Cell. Mol. Med.* **2020**, *24*, 5955–5965. [CrossRef]
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142. Ma, X.; Svegliati-Baroni, G.; Poniachik, J.; Baraona, E.; Lieber, C.S. Collagen Synthesis by Liver Stellate Cells Is Released from Its Normal Feedback Regulation by Acetaldehyde-Induced Modification of the Carboxyl-Terminal Propeptide of Procollagen. *Alcohol. Clin. Exp. Res.* **1997**, *21*, 1204-1211. [CrossRef] [PubMed]

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144. Thiele, G.M.; Duryee, M.J.; Willis, M.S.; Sorrell, M.F.; Freeman, T.L.; Tuma, D.J.; Klassen, L.W. Malondialdehyde-Acetaldehyde (MAA) Modified Proteins Induce pro-Inflammatory and pro-Fibrotic Responses by Liver Endothelial Cells. *Comp. Hepatol.* **2004**, *3* (Suppl. 1), S25. [CrossRef] [PubMed]

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142. Ma, X.; Svegliati-Baroni, G.; Poniachik, J.; Baraona, E.; Lieber, C.S. Collagen Synthesis by Liver Stellate Cells Is Released from Its Normal Feedback Regulation by Acetaldehyde-Induced Modification of the Carboxyl-Terminal Propeptide of Procollagen. *Alcohol. Clin. Exp. Res.* **1997**, *21*, 1204-1211. [CrossRef] [PubMed]

143. Niemelä, O.; Parkkila, S.; Ylä-Herttuala, S.; Halsted, C.; Witztum, J.L.; Lanca, A.; Israel, Y. Covalent Protein Adducts in the Liver as a Result of Ethanol Metabolism and Lipid Peroxidation. *Lab. Investig. J. Tech. Methods Pathol.* **1994**, *70*, 537-546.

144. Thiele, G.M.; Duryee, M.J.; Willis, M.S.; Sorrell, M.F.; Freeman, T.L.; Tuma, D.J.; Klassen, L.W. Malondialdehyde-Acetaldehyde (MAA) Modified Proteins Induce pro-Inflammatory and pro-Fibrotic Responses by Liver Endothelial Cells. *Comp. Hepatol.* **2004**, *3* (Suppl. 1), S25. [CrossRef] [PubMed]

145. Yan, A.W.; Schnabl, B. Bacterial Translocation and Changes in the Intestinal Microbiome Associated with Alcoholic Liver Disease. *World J. Hepatol.* **2012**, *4*, 110-118. [CrossRef] [PubMed]

146. Rao, R. Endotoxemia and Gut Barrier Dysfunction in Alcoholic Liver Disease. *Hepatol. Baltim. Md* **2009**, *50*, 638-644. [CrossRef] [PubMed]

147. Petrasek, J.; Csak, T.; Szabo, G. Toll-like Receptors in Liver Disease. *Adv. Clin. Chem.* **2013**, *59*, 155-201. [CrossRef]

148. Takano, T.; Abe, S.; Hata, S. A Selected Ion Monitoring Method for Quantifying Simvastatin and Its Acid Form in Human Plasma, Using the Ferroceneboronate Derivative. *Biomed. Environ. Mass Spectrom.* **1990**, *19*, 577-581. [CrossRef]

149. Gao, B.; Bataller, R. Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets. *Gastroenterology* **2011**, *141*, 1572-1585. [CrossRef]

150. Nagy, L.E. The Role of Innate Immunity in Alcoholic Liver Disease. *Alcohol Res. Curr. Rev.* **2015**, *37*, 237-250.

151. Gao, B.; Ahmad, M.F.; Nagy, L.E.; Tsukamoto, H. Inflammatory Pathways in Alcoholic Steatohepatitis. *J. Hepatol.* **2019**, *70*, 249-259. [CrossRef] [PubMed]

152. Bala, S.; Csak, T.; Kodys, K.; Catalano, D.; Ambade, A.; Furi, I.; Lowe, P.; Cho, Y.; Iracheta-Vellve, A.; Szabo, G. Alcohol-Induced MiR-155 and HDAC11 Inhibit Negative Regulators of the TLR4 Pathway and Lead to Increased LPS Responsiveness of Kupffer Cells in Alcoholic Liver Disease. *J. Leukoc. Biol.* **2017**, *102*, 487-498. [CrossRef] [PubMed]

153. Bala, S.; Petrasek, J.; Mundkur, S.; Catalano, D.; Levin, I.; Ward, J.; Alao, H.; Kodys, K.; Szabo, G. Circulating MicroRNAs in Exosomes Indicate Hepatocyte Injury and Inflammation in Alcoholic, Drug-Induced, and Inflammatory Liver Diseases. *Hepatol. Baltim. Md* **2012**, *56*, 1946-1957. [CrossRef]

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260. Wang, S.; Zhang, S.; He, Y.; Huang, X.; Hui, Y.; Tang, Y. HOXA11-AS Regulates JAK-STAT Pathway by MiR-15a-3p/STAT3 Axis to Promote the Growth and Metastasis in Liver Cancer. *J. Cell. Biochem.* **2019**, *120*, 15941–15951. [CrossRef]

261. Lin, Z.; Liu, J. LncRNA DQ786243 Promotes Hepatocellular Carcinoma Cell Invasion and Proliferation by Regulating the MiR-15b-5p/Wnt3A Axis. *Mol. Med. Rep.* **2021**, *23*, 318. [CrossRef]

262. Pan, W.; Wang, L.; Zhang, X.-F.; Zhang, H.; Zhang, J.; Wang, G.; Xu, P.; Zhang, Y.; Hu, P.; Zhang, X.-D.; et al. Hypoxia-Induced MicroRNA-191 Contributes to Hepatic Ischemia/Reperfusion Injury through the ZONAB/Cyclin D1 Axis. *Cell Death Differ.* **2019**, *26*, 291–305. [CrossRef]

263. Fornari, F.; Milazzo, M.; Chieco, P.; Negrini, M.; Calin, G.A.; Grazi, G.L.; Pollutri, D.; Croce, C.M.; Bolondi, L.; Gramantieri, L. MiR-199a-3p Regulates MTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells. *Cancer Res.* **2010**, *70*, 5184–5193. [CrossRef]

264. Henry, J.C.; Park, J.-K.; Jiang, J.; Kim, J.H.; Nagorney, D.M.; Roberts, L.R.; Banerjee, S.; Schmittgen, T.D. MiR-199a-3p Targets CD44 and Reduces Proliferation of CD44 Positive Hepatocellular Carcinoma Cell Lines. *Biochem. Biophys. Res. Commun.* **2010**, *403*, 120–125. [CrossRef] [PubMed]

265. Guan, J.; Liu, Z.; Xiao, M.; Hao, F.; Wang, C.; Chen, Y.; Lu, Y.; Liang, J. MicroRNA-199a-3p Inhibits Tumorigenesis of Hepatocellular Carcinoma Cells by Targeting ZHX1/PUMA Signal. *Am. J. Transl. Res.* **2017**, *9*, 2457–2465. [PubMed]

266. Zhang, J.; Yang, Y.; Yang, T.; Liu, Y.; Li, A.; Fu, S.; Wu, M.; Pan, Z.; Zhou, W. MicroRNA-22, Downregulated in Hepatocellular Carcinoma and Correlated with Prognosis, Suppresses Cell Proliferation and Tumourigenicity. *Br. J. Cancer* **2010**, *103*, 1215–1220. [CrossRef] [PubMed]

267. Hu, Y.; Setayesh, T.; Vaziri, F.; Wu, X.; Hwang, S.T.; Chen, X.; Yvonne Wan, Y.-J. MiR-22 Gene Therapy Treats HCC by Promoting Anti-Tumor Immunity and Enhancing Metabolism. *Mol. Ther. J. Am. Soc. Gene Ther.* **2023**, *31*, 1829–1845. [CrossRef] [PubMed]

268. Shi, C.; Xu, X. MicroRNA-22 Is down-Regulated in Hepatitis B Virus-Related Hepatocellular Carcinoma. *Biomed. Pharmacother. Biomedecine Pharmacother.* **2013**, *67*, 375–380. [CrossRef]

269. Yang, Y.-F.; Wang, F.; Xiao, J.-J.; Song, Y.; Zhao, Y.-Y.; Cao, Y.; Bei, Y.-H.; Yang, C.-Q. MiR-222 Overexpression Promotes Proliferation of Human Hepatocellular Carcinoma HepG2 Cells by Downregulating P27. *Int. J. Clin. Exp. Med.* **2014**, *7*, 893–902.
246. Wang, L.; Zhang, X.; Jia, L.-T.; Hu, S.-J.; Zhao, J.; Yang, J.-D.; Wen, W.-H.; Wang, Z.; Wang, T.; Zhao, J.; et al. C-Myc-Mediated Epigenetic Silencing of MicroRNA-101 Contributes to Dysregulation of Multiple Pathways in Hepatocellular Carcinoma. *Hepatol. Baltim. Md* **2014**, *59*, 1850–1863. [CrossRef] [PubMed]

247. He, H.; Tian, W.; Chen, H.; Deng, Y. MicroRNA-101 Sensitizes Hepatocellular Carcinoma Cells to Doxorubicin-Induced Apoptosis via Targeting Mcl-1. *Mol. Med. Rep.* **2016**, *13*, 1923–1929. [CrossRef] [PubMed]

248. Chiang, C.-W.; Huang, Y.; Leong, K.-W.; Chen, L.-C.; Chen, H.-C.; Chen, S.-J.; Chou, C.-K. PKCalpha Mediated Induction of MiR-101 in Human Hepatoma HepG2 Cells. *J. Biomed. Sci.* **2010**, *17*, 35. [CrossRef]

249. Yang, J.; Lu, Y.; Lin, Y.-Y.; Zheng, Z.-Y.; Fang, J.-H.; He, S.; Zhuang, S.-M. Vascular Mimicry Formation Is Promoted by Paracrine TGF-β and SDF1 of Cancer-Associated Fibroblasts and Inhibited by MiR-101 in Hepatocellular Carcinoma. *Cancer Lett.* **2016**, *383*, 18–27. [CrossRef]

250. Yuan, R.; Zhi, Q.; Zhao, H.; Han, Y.; Gao, L.; Wang, B.; Kou, Z.; Guo, Z.; He, S.; Xue, X.; et al. Upregulated Expression of MiR-106a by DNA Hypomethylation Plays an Oncogenic Role in Hepatocellular Carcinoma. *Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med.* **2015**, *36*, 3093–3100. [CrossRef]

251. Gao, J.; Dai, C.; Yu, X.; Yin, X.-B.; Zhou, F. Long Noncoding RNA LEF1-AS1 Acts as a MicroRNA-10a-5p Regulator to Enhance MSI1 Expression and Promote Chemoresistance in Hepatocellular Carcinoma Cells through Activating AKT Signaling Pathway. *J. Cell. Biochem.* **2021**, *122*, 86–99. [CrossRef]

252. Gong, J.; Zhang, J.-P.; Li, B.; Zeng, C.; You, K.; Chen, M.-X.; Yuan, Y.; Zhuang, S.-M. MicroRNA-125b Promotes Apoptosis by Regulating the Expression of Mcl-1, Bcl-w and IL-6R. *Oncogene* **2013**, *32*, 3071–3079. [CrossRef]

253. Song, S.; Yang, Y.; Liu, M.; Liu, B.; Yang, X.; Yu, M.; Qi, H.; Ren, M.; Wang, Z.; Zou, J.; et al. MiR-125b Attenuates Human Hepatocellular Carcinoma Malignancy through Targeting SIRT6. *Am. J. Cancer Res.* **2018**, *8*, 993–1007.

254. Zhao, L.; Wang, W. MiR-125b Suppresses the Proliferation of Hepatocellular Carcinoma Cells by Targeting Sirtuin7. *Int. J. Clin. Exp. Med.* **2015**, *8*, 18469–18475. [PubMed]

255. Jiang, F.; Mu, J.; Wang, X.; Ye, X.; Si, L.; Ning, S.; Li, Z.; Li, Y. The Repressive Effect of MiR-148a on TGF Beta-SMADs Signal Pathway Is Involved in the Glabridin-Induced Inhibition of the Cancer Stem Cells-like Properties in Hepatocellular Carcinoma Cells. *PLoS ONE* **2014**, *9*, e96698. [CrossRef] [PubMed]

256. You, Z.; Peng, D.; Cao, Y.; Zhu, Y.; Yin, J.; Zhang, G.; Peng, X. P53 Suppresses the Progression of Hepatocellular Carcinoma via MiR-15a by Decreasing OGT Expression and EZH2 Stabilization. *J. Cell. Mol. Med.* **2021**, *25*, 9168–9182. [CrossRef] [PubMed]

257. Wang, Y. The Inhibition of MicroRNA-15a Suppresses Hepatitis B Virus-Associated Liver Cancer Cell Growth through the Smad/TGF-β Pathway. *Oncol. Rep.* **2017**, *37*, 3520–3526. [CrossRef] [PubMed]

258. Liu, N.; Jiao, T.; Huang, Y.; Liu, W.; Li, Z.; Ye, X. Hepatitis B Virus Regulates Apoptosis and Tumorigenesis through the MicroRNA-15a-Smad7-Transforming Growth Factor Beta Pathway. *J. Virol.* **2015**, *89*, 2739–2749. [CrossRef] [PubMed]

259. Tian, X.; Wu, Y.; Yang, Y.; Wang, J.; Niu, M.; Gao, S.; Qin, T.; Bao, D. Long Noncoding RNA LINC00662 Promotes M2 Macrophage Polarization and Hepatocellular Carcinoma Progression via Activating Wnt/β-Catenin Signaling. *Mol. Oncol.* **2020**, *14*, 462–483. [CrossRef] [PubMed]

260. Wang, S.; Zhang, S.; He, Y.; Huang, X.; Hui, Y.; Tang, Y. HOXA11-AS Regulates JAK-STAT Pathway by MiR-15a-3p/STAT3 Axis to Promote the Growth and Metastasis in Liver Cancer. *J. Cell. Biochem.* **2019**, *120*, 15941–15951. [CrossRef]

261. Lin, Z.; Liu, J. LncRNA DQ786243 Promotes Hepatocellular Carcinoma Cell Invasion and Proliferation by Regulating the MiR-15b-5p/Wnt3A Axis. *Mol. Med. Rep.* **2021**, *23*, 318. [CrossRef]

262. Pan, W.; Wang, L.; Zhang, X.-F.; Zhang, H.; Zhang, J.; Wang, G.; Xu, P.; Zhang, Y.; Hu, P.; Zhang, X.-D.; et al. Hypoxia-Induced MicroRNA-191 Contributes to Hepatic Ischemia/Reperfusion Injury through the ZONAB/Cyclin D1 Axis. *Cell Death Differ.* **2019**, *26*, 291–305. [CrossRef]

263. Fornari, F.; Milazzo, M.; Chieco, P.; Negrini, M.; Calin, G.A.; Grazi, G.L.; Pollutri, D.; Croce, C.M.; Bolondi, L.; Gramantieri, L. MiR-199a-3p Regulates MTOR and c-Met to Influence the Doxorubicin Sensitivity of Human Hepatocarcinoma Cells. *Cancer Res.* **2010**, *70*, 5184–5193. [CrossRef]

264. Henry, J.C.; Park, J.-K.; Jiang, J.; Kim, J.H.; Nagorney, D.M.; Roberts, L.R.; Banerjee, S.; Schmittgen, T.D. MiR-199a-3p Targets CD44 and Reduces Proliferation of CD44 Positive Hepatocellular Carcinoma Cell Lines. *Biochem. Biophys. Res. Commun.* **2010**, *403*, 120–125. [CrossRef] [PubMed]

265. Guan, J.; Liu, Z.; Xiao, M.; Hao, F.; Wang, C.; Chen, Y.; Lu, Y.; Liang, J. MicroRNA-199a-3p Inhibits Tumorigenesis of Hepatocellular Carcinoma Cells by Targeting ZHX1/PUMA Signal. *Am. J. Transl. Res.* **2017**, *9*, 2457–2465. [PubMed]

266. Zhang, J.; Yang, Y.; Yang, T.; Liu, Y.; Li, A.; Fu, S.; Wu, M.; Pan, Z.; Zhou, W. MicroRNA-22, Downregulated in Hepatocellular Carcinoma and Correlated with Prognosis, Suppresses Cell Proliferation and Tumourigenicity. *Br. J. Cancer* **2010**, *103*, 1215–1220. [CrossRef] [PubMed]

267. Hu, Y.; Setayesh, T.; Vaziri, F.; Wu, X.; Hwang, S.T.; Chen, X.; Yvonne Wan, Y.-J. MiR-22 Gene Therapy Treats HCC by Promoting Anti-Tumor Immunity and Enhancing Metabolism. *Mol. Ther. J. Am. Soc. Gene Ther.* **2023**, *31*, 1829–1845. [CrossRef] [PubMed]

268. Shi, C.; Xu, X. MicroRNA-22 Is down-Regulated in Hepatitis B Virus-Related Hepatocellular Carcinoma. *Biomed. Pharmacother. Biomedecine Pharmacother.* **2013**, *67*, 375–380. [CrossRef]

269. Yang, Y.-F.; Wang, F.; Xiao, J.-J.; Song, Y.; Zhao, Y.-Y.; Cao, Y.; Bei, Y.-H.; Yang, C.-Q. MiR-222 Overexpression Promotes Proliferation of Human Hepatocellular Carcinoma HepG2 Cells by Downregulating P27. *Int. J. Clin. Exp. Med.* **2014**, *7*, 893–902.
270. Wong, Q.W.-L.; Ching, A.K.-K.; Chan, A.W.-H.; Choy, K.-W.; To, K.-F.; Lai, P.B.-S.; Wong, N. MiR-222 Overexpression Confers Cell Migratory Advantages in Hepatocellular Carcinoma through Enhancing AKT Signaling. *Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.* **2010**, *16*, 867–875. [CrossRef]

271. Ma, D.; Tao, X.; Gao, F.; Fan, C.; Wu, D. MiR-224 Functions as an Onco-MiRNA in Hepatocellular Carcinoma Cells by Activating AKT Signaling. *Oncol. Lett.* **2012**, *4*, 483–488. [CrossRef]

272. An, F.; Wu, X.; Zhang, Y.; Chen, D.; Lin, Y.; Wu, F.; Ding, J.; Xia, M.; Zhan, Q. MiR-224 Regulates the Aggressiveness of Hepatoma Cells Through the IL-6/STAT3/SMAD4 Pathway. *Turk. J. Gastroenterol. Off. J. Turk. Soc. Gastroenterol.* **2021**, *32*, 532–542. [CrossRef]

273. Wang, Y.; Ren, J.; Gao, Y.; Ma, J.Z.I.; Toh, H.C.; Chow, P.; Chung, A.Y.F.; Ooi, L.L.P.J.; Lee, C.G.L. MicroRNA-224 Targets SMAD Family Member 4 to Promote Cell Proliferation and Negatively Influence Patient Survival. *PLoS ONE* **2013**, *8*, e68744. [CrossRef]

274. Cao, Y.; Lv, W.; Ding, W.; Li, J. Sevoflurane Inhibits the Proliferation and Invasion of Hepatocellular Carcinoma Cells through Regulating the PTEN/Akt/GSK-3β/B-catenin Signaling Pathway by Downregulating MiR-25-3p. *Int. J. Mol. Med.* **2020**, *46*, 97–106. [CrossRef] [PubMed]

275. Cheng, H.; Xue, J.; Yang, S.; Chen, Y.; Wang, Y.; Zhu, Y.; Wang, X.; Kuang, D.; Ruan, Q.; Duan, Y.; et al. Co-Targeting of IGF1R/MTOR Pathway by MiR-497 and MiR-99a Impairs Hepatocellular Carcinoma Development. *Oncotarget* **2017**, *8*, 47984–47997. [CrossRef] [PubMed]

276. Li, D.; Liu, X.; Lin, L.; Hou, J.; Li, N.; Wang, C.; Wang, P.; Zhang, Q.; Zhang, P.; Zhou, W.; et al. MicroRNA-99a Inhibits Hepatocellular Carcinoma Growth and Correlates with Prognosis of Patients with Hepatocellular Carcinoma. *J. Biol. Chem.* **2011**, *286*, 36677–36685. [CrossRef] [PubMed]

277. Zhang, J.; Jin, H.; Liu, H.; Lv, S.; Wang, B.; Wang, R.; Liu, H.; Ding, M.; Yang, Y.; Li, L.; et al. MiRNA-99a Directly Regulates AGO2 through Translational Repression in Hepatocellular Carcinoma. *Oncogenesis* **2014**, *3*, e97. [CrossRef] [PubMed]

278. Fu, Y.; Chen, J.; Huang, Z. Recent Progress in MicroRNA-Based Delivery Systems for the Treatment of Human Disease. *ExRNA* **2019**, *1*, 24. [CrossRef]

279. To, K.K.W.; Fong, W.; Tong, C.W.S.; Wu, M.; Yan, W.; Cho, W.C.S. Advances in the Discovery of MicroRNA-Based Anticancer Therapeutics: Latest Tools and Developments. *Expert Opin. Drug Discov.* **2020**, *15*, 63–83. [CrossRef] [PubMed]

280. Liu, D.; Wan, X.; Shan, X.; Fan, R.; Zha, W. Drugging the "Undruggable" MicroRNAs. *Cell. Mol. Life Sci.* **2021**, *78*, 1861–1871. [CrossRef]

281. Krichevsky, A.; Nguyen, L.; Wei, Z.; Silva, M.; Barberán-Soler, S.; Rabinovsky, R.; Muratore, C.; Stricker, J.; Hortman, C.; Young-Pearse, T.; et al. Small Molecule Regulators of MicroRNAs Identified by High-Throughput Screen Coupled with High-Throughput Sequencing. *Res. Sq.* 2023, preprint. [CrossRef]

282. Dasgupta, I.; Chatterjee, A. Recent Advances in MiRNA Delivery Systems. *Methods Protoc.* **2021**, *4*, 10. [CrossRef]

283. Pan, Y.; Zhang, Y.; Jia, T.; Zhang, K.; Li, J.; Wang, L. Development of a MicroRNA Delivery System Based on Bacteriophage MS2 Virus-like Particles. *FEBS J.* **2012**, *279*, 1198–1208. [CrossRef]

284. Sun, Y.; Sun, Y.; Zhao, R. Establishment of MicroRNA Delivery System by PP7 Bacteriophage-like Particles Carrying Cell-Penetrating Peptide. *J. Biosci. Bioeng.* **2017**, *124*, 242–249. [CrossRef] [PubMed]

285. Zhang, J.; Li, D.; Zhang, R.; Peng, R.; Li, J. Delivery of MicroRNA-21-Sponge and Pre-MicroRNA-122 by MS2 Virus-like Particles to Therapeutically Target Hepatocellular Carcinoma Cells. *Exp. Biol. Med. Maywood NJ* **2021**, *246*, 2463–2472. [CrossRef] [PubMed]

286. Chan, S.K.; Steinmetz, N.F. MicroRNA-181a Silencing by Antisense Oligonucleotides Delivered by Virus-like Particles. *J. Mater. Chem. B* **2023**, *11*, 816–825. [CrossRef] [PubMed]

287. Vandenberghe, L.H.; Wilson, J.M. AAV as an Immunogen. *Curr. Gene Ther.* **2007**, *7*, 325–333. [CrossRef] [PubMed]

288. Verdera, H.C.; Kuranda, K.; Mingozzi, F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. *Mol. Ther. J. Am. Soc. Gene Ther.* **2020**, *28*, 723–746. [CrossRef] [PubMed]

289. Munir, J.; Yoon, J.K.; Ryu, S. Therapeutic MiRNA-Enriched Extracellular Vesicles: Current Approaches and Future Prospects. *Cells* **2020**, *9*, 2271. [CrossRef] [PubMed]

290. Shinde, S.S.; Ahmed, S.; Malik, J.A.; Hani, U.; Khanam, A.; Ashraf Bhat, F.; Ahmad Mir, S.; Ghazwani, M.; Wahab, S.; Haider, N.; et al. Therapeutic Delivery of Tumor Suppressor MiRNAs for Breast Cancer Treatment. *Biology* **2023**, *12*, 467. [CrossRef]

291. Böttger, R.; Pauli, G.; Chao, P.-H.; Al Fayez, N.; Hohenwarter, L.; Li, S.-D. Lipid-Based Nanoparticle Technologies for Liver Targeting. *Adv. Drug Deliv. Rev.* **2020**, *154–155*, 79–101. [CrossRef]

292. Luo, F.; Yu, Y.; Li, M.; Chen, Y.; Zhang, P.; Xiao, C.; Lv, G. Polymeric Nanomedicines for the Treatment of Hepatic Diseases. *J. Nanobiotechnol.* **2022**, *20*, 488. [CrossRef]

293. Scott, L.J. Givosiran: First Approval. *Drugs* **2020**, *80*, 335–339. [CrossRef]

294. Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.-X.; Diehl, A.M. Inhibiting Triglyceride Synthesis Improves Hepatic Steatosis but Exacerbates Liver Damage and Fibrosis in Obese Mice with Nonalcoholic Steatohepatitis. *Hepatol. Baltim. Md* **2007**, *45*, 1366–1374. [CrossRef] [PubMed]

295. Listenberger, L.L.; Han, X.; Lewis, S.E.; Cases, S.; Farese, R.V.; Ory, D.S.; Schaffer, J.E. Triglyceride Accumulation Protects against Fatty Acid-Induced Lipotoxicity. *Proc. Natl. Acad. Sci. USA* **2003**, *100*, 3077–3082. [CrossRef] [PubMed]

296. Parlati, L.; Régnier, M.; Guillou, H.; Postic, C. New Targets for NAFLD. *JHEP Rep. Innov. Hepatol.* **2021**, *3*, 100346. [CrossRef] [PubMed]
270. Wong, Q.W.-L.; Ching, A.K.-K.; Chan, A.W.-H.; Choy, K.-W.; To, K.-F.; Lai, P.B.-S.; Wong, N. MiR-222 Overexpression Confers Cell Migratory Advantages in Hepatocellular Carcinoma through Enhancing AKT Signaling. *Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res.* **2010**, *16*, 867–875. [CrossRef]

271. Ma, D.; Tao, X.; Gao, F.; Fan, C.; Wu, D. MiR-224 Functions as an Onco-MiRNA in Hepatocellular Carcinoma Cells by Activating AKT Signaling. *Oncol. Lett.* **2012**, *4*, 483–488. [CrossRef]

272. An, F.; Wu, X.; Zhang, Y.; Chen, D.; Lin, Y.; Wu, F.; Ding, J.; Xia, M.; Zhan, Q. MiR-224 Regulates the Aggressiveness of Hepatoma Cells Through the IL-6/STAT3/SMAD4 Pathway. *Turk. J. Gastroenterol. Off. J. Turk. Soc. Gastroenterol.* **2021**, *32*, 532–542. [CrossRef]

273. Wang, Y.; Ren, J.; Gao, Y.; Ma, J.Z.I.; Toh, H.C.; Chow, P.; Chung, A.Y.F.; Ooi, L.L.P.J.; Lee, C.G.L. MicroRNA-224 Targets SMAD Family Member 4 to Promote Cell Proliferation and Negatively Influence Patient Survival. *PLoS ONE* **2013**, *8*, e68744. [CrossRef]

274. Cao, Y.; Lv, W.; Ding, W.; Li, J. Sevoflurane Inhibits the Proliferation and Invasion of Hepatocellular Carcinoma Cells through Regulating the PTEN/Akt/GSK-3β/B-catenin Signaling Pathway by Downregulating MiR-25-3p. *Int. J. Mol. Med.* **2020**, *46*, 97–106. [CrossRef] [PubMed]

275. Cheng, H.; Xue, J.; Yang, S.; Chen, Y.; Wang, Y.; Zhu, Y.; Wang, X.; Kuang, D.; Ruan, Q.; Duan, Y.; et al. Co-Targeting of IGF1R/MTOR Pathway by MiR-497 and MiR-99a Impairs Hepatocellular Carcinoma Development. *Oncotarget* **2017**, *8*, 47984–47997. [CrossRef] [PubMed]

276. Li, D.; Liu, X.; Lin, L.; Hou, J.; Li, N.; Wang, C.; Wang, P.; Zhang, Q.; Zhang, P.; Zhou, W.; et al. MicroRNA-99a Inhibits Hepatocellular Carcinoma Growth and Correlates with Prognosis of Patients with Hepatocellular Carcinoma. *J. Biol. Chem.* **2011**, *286*, 36677–36685. [CrossRef] [PubMed]

277. Zhang, J.; Jin, H.; Liu, H.; Lv, S.; Wang, B.; Wang, R.; Liu, H.; Ding, M.; Yang, Y.; Li, L.; et al. MiRNA-99a Directly Regulates AGO2 through Translational Repression in Hepatocellular Carcinoma. *Oncogenesis* **2014**, *3*, e97. [CrossRef] [PubMed]

278. Fu, Y.; Chen, J.; Huang, Z. Recent Progress in MicroRNA-Based Delivery Systems for the Treatment of Human Disease. *ExRNA* **2019**, *1*, 24. [CrossRef]

279. To, K.K.W.; Fong, W.; Tong, C.W.S.; Wu, M.; Yan, W.; Cho, W.C.S. Advances in the Discovery of MicroRNA-Based Anticancer Therapeutics: Latest Tools and Developments. *Expert Opin. Drug Discov.* **2020**, *15*, 63–83. [CrossRef] [PubMed]

280. Liu, D.; Wan, X.; Shan, X.; Fan, R.; Zha, W. Drugging the "Undruggable" MicroRNAs. *Cell. Mol. Life Sci.* **2021**, *78*, 1861–1871. [CrossRef]

281. Krichevsky, A.; Nguyen, L.; Wei, Z.; Silva, M.; Barberán-Soler, S.; Rabinovsky, R.; Muratore, C.; Stricker, J.; Hortman, C.; Young-Pearse, T.; et al. Small Molecule Regulators of MicroRNAs Identified by High-Throughput Screen Coupled with High-Throughput Sequencing. *Res. Sq.* 2023, preprint. [CrossRef]

282. Dasgupta, I.; Chatterjee, A. Recent Advances in MiRNA Delivery Systems. *Methods Protoc.* **2021**, *4*, 10. [CrossRef]

283. Pan, Y.; Zhang, Y.; Jia, T.; Zhang, K.; Li, J.; Wang, L. Development of a MicroRNA Delivery System Based on Bacteriophage MS2 Virus-like Particles. *FEBS J.* **2012**, *279*, 1198–1208. [CrossRef]

284. Sun, Y.; Sun, Y.; Zhao, R. Establishment of MicroRNA Delivery System by PP7 Bacteriophage-like Particles Carrying Cell-Penetrating Peptide. *J. Biosci. Bioeng.* **2017**, *124*, 242–249. [CrossRef] [PubMed]

285. Zhang, J.; Li, D.; Zhang, R.; Peng, R.; Li, J. Delivery of MicroRNA-21-Sponge and Pre-MicroRNA-122 by MS2 Virus-like Particles to Therapeutically Target Hepatocellular Carcinoma Cells. *Exp. Biol. Med. Maywood NJ* **2021**, *246*, 2463–2472. [CrossRef] [PubMed]

286. Chan, S.K.; Steinmetz, N.F. MicroRNA-181a Silencing by Antisense Oligonucleotides Delivered by Virus-like Particles. *J. Mater. Chem. B* **2023**, *11*, 816–825. [CrossRef] [PubMed]

287. Vandenberghe, L.H.; Wilson, J.M. AAV as an Immunogen. *Curr. Gene Ther.* **2007**, *7*, 325–333. [CrossRef] [PubMed]

288. Verdera, H.C.; Kuranda, K.; Mingozzi, F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. *Mol. Ther. J. Am. Soc. Gene Ther.* **2020**, *28*, 723–746. [CrossRef] [PubMed]

289. Munir, J.; Yoon, J.K.; Ryu, S. Therapeutic MiRNA-Enriched Extracellular Vesicles: Current Approaches and Future Prospects. *Cells* **2020**, *9*, 2271. [CrossRef] [PubMed]

290. Shinde, S.S.; Ahmed, S.; Malik, J.A.; Hani, U.; Khanam, A.; Ashraf Bhat, F.; Ahmad Mir, S.; Ghazwani, M.; Wahab, S.; Haider, N.; et al. Therapeutic Delivery of Tumor Suppressor MiRNAs for Breast Cancer Treatment. *Biology* **2023**, *12*, 467. [CrossRef]

291. Böttger, R.; Pauli, G.; Chao, P.-H.; Al Fayez, N.; Hohenwarter, L.; Li, S.-D. Lipid-Based Nanoparticle Technologies for Liver Targeting. *Adv. Drug Deliv. Rev.* **2020**, *154–155*, 79–101. [CrossRef]

292. Luo, F.; Yu, Y.; Li, M.; Chen, Y.; Zhang, P.; Xiao, C.; Lv, G. Polymeric Nanomedicines for the Treatment of Hepatic Diseases. *J. Nanobiotechnol.* **2022**, *20*, 488. [CrossRef]

293. Scott, L.J. Givosiran: First Approval. *Drugs* **2020**, *80*, 335–339. [CrossRef]

294. Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.-X.; Diehl, A.M. Inhibiting Triglyceride Synthesis Improves Hepatic Steatosis but Exacerbates Liver Damage and Fibrosis in Obese Mice with Nonalcoholic Steatohepatitis. *Hepatol. Baltim. Md* **2007**, *45*, 1366–1374. [CrossRef] [PubMed]

295. Listenberger, L.L.; Han, X.; Lewis, S.E.; Cases, S.; Farese, R.V.; Ory, D.S.; Schaffer, J.E. Triglyceride Accumulation Protects against Fatty Acid-Induced Lipotoxicity. *Proc. Natl. Acad. Sci. USA* **2003**, *100*, 3077–3082. [CrossRef] [PubMed]

296. Parlati, L.; Régnier, M.; Guillou, H.; Postic, C. New Targets for NAFLD. *JHEP Rep. Innov. Hepatol.* **2021**, *3*, 100346. [CrossRef] [PubMed]
297. Wang, X.; Yu, B.; Ren, W.; Mo, X.; Zhou, C.; He, H.; Jia, H.; Wang, L.; Jacob, S.T.; Lee, R.J.; et al. Enhanced Hepatic Delivery of SiRNA and MicroRNA Using Oleic Acid Based Lipid Nanoparticle Formulations. *J. Control. Release Off. J. Control. Release Soc.* **2013**, *172*, 690–698. [CrossRef] [PubMed]

298. Ellipilli, S.; Wang, H.; Binzel, D.W.; Shu, D.; Guo, P. Ligand-Displaying-Exosomes Using RNA Nanotechnology for Targeted Delivery of Multi-Specific Drugs for Liver Cancer Regression. *Nanomed. Nanotechnol. Biol. Med.* **2023**, *50*, 102667. [CrossRef] [PubMed]

299. Gu, L.; Zhang, F.; Wu, J.; Zhuge, Y. Nanotechnology in Drug Delivery for Liver Fibrosis. *Front. Mol. Biosci.* **2021**, *8*, 804396. [CrossRef]

300. Kim, A.; Saikia, P.; Nagy, L.E. MiRNAs Involved in M1/M2 Hyperpolarization Are Clustered and Coordinately Expressed in Alcoholic Hepatitis. *Front. Immunol.* **2019**, *10*, 1295. [CrossRef]

301. Zeng, T.; Zhang, C.-L.; Xiao, M.; Yang, R.; Xie, K.-Q. Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials. *Front. Immunol.* **2016**, *7*, 538. [CrossRef]

302. Hong, D.S.; Kang, Y.-K.; Borad, M.; Sachdev, J.; Ejadi, S.; Lim, H.Y.; Brenner, A.J.; Park, K.; Lee, J.-L.; Kim, T.-Y.; et al. Phase 1 Study of MRX34, a Liposomal MiR-34a Mimic, in Patients with Advanced Solid Tumours. *Br. J. Cancer* **2020**, *122*, 1630–1637. [CrossRef]

303. Cheng, S.-H.; Li, F.-C.; Souris, J.S.; Yang, C.-S.; Tseng, F.-G.; Lee, H.-S.; Chen, C.-T.; Dong, C.-Y.; Lo, L.-W. Visualizing Dynamics of Sub-Hepatic Distribution of Nanoparticles Using Intravital Multiphoton Fluorescence Microscopy. *ACS Nano* **2012**, *6*, 4122–4131. [CrossRef]

304. Shilpi, S. Drug Targeting Strategies for Liver Cancer and Other Liver Diseases. *MOJ Drug Des. Dev. Ther.* **2018**, *2*, 171–177. [CrossRef]

305. Hanna, J.; Hossain, G.S.; Kocerha, J. The Potential for MicroRNA Therapeutics and Clinical Research. *Front. Genet.* **2019**, *10*, 478. [CrossRef] [PubMed]

306. Chakraborty, C.; Sharma, A.R.; Sharma, G.; Lee, S.-S. Therapeutic Advances of MiRNAs: A Preclinical and Clinical Update. *J. Adv. Res.* **2021**, *28*, 127–138. [CrossRef] [PubMed]

307. Iacomino, G. MiRNAs: The Road from Bench to Bedside. *Genes* **2023**, *14*, 314. [CrossRef]

308. Roberts, T.C.; Langer, R.; Wood, M.J.A. Advances in Oligonucleotide Drug Delivery. *Nat. Rev. Drug Discov.* **2020**, *19*, 673–694. [CrossRef]

309. Kim, T.; Croce, C.M. MicroRNA: Trends in Clinical Trials of Cancer Diagnosis and Therapy Strategies. *Exp. Mol. Med.* **2023**, *55*, 1314–1321. [CrossRef]

310. Chakraborty, C.; Sharma, A.R.; Sharma, G.; Doss, C.G.P.; Lee, S.-S. Therapeutic MiRNA and SiRNA: Moving from Bench to Clinic as Next Generation Medicine. *Mol. Ther. Nucleic Acids* **2017**, *8*, 132–143. [CrossRef]

311. Hsu, S.-H.; Yu, B.; Wang, X.; Lu, Y.; Schmidt, C.R.; Lee, R.J.; Lee, L.J.; Jacob, S.T.; Ghoshal, K. Cationic Lipid Nanoparticles for Therapeutic Delivery of SiRNA and MiRNA to Murine Liver Tumor. *Nanomed. Nanotechnol. Biol. Med.* **2013**, *9*, 1169–1180. [CrossRef]

312. Yang, C.; Yin, M.; Xu, G.; Lin, W.-J.; Chen, J.; Zhang, Y.; Feng, T.; Huang, P.; Chen, C.-K.; Yong, K.-T. Biodegradable Polymers as a Noncoding MiRNA Nanocarrier for Multiple Targeting Therapy of Human Hepatocellular Carcinoma. *Adv. Healthc. Mater.* **2019**, *8*, e1801318. [CrossRef]

313. Ning, Q.; Liu, Y.-F.; Ye, P.-J.; Gao, P.; Li, Z.-P.; Tang, S.-Y.; He, D.-X.; Tang, S.-S.; Wei, H.; Yu, C.-Y. Delivery of Liver-Specific MiRNA-122 Using a Targeted Macromolecular Prodrug toward Synergistic Therapy for Hepatocellular Carcinoma. *ACS Appl. Mater. Interfaces* **2019**, *11*, 10578–10588. [CrossRef]

314. Li, Y.; Luan, Y.; Li, J.; Song, H.; Li, Y.; Qi, H.; Sun, B.; Zhang, P.; Wu, X.; Liu, X.; et al. Exosomal MiR-199a-5p Promotes Hepatic Lipid Accumulation by Modulating MST1 Expression and Fatty Acid Metabolism. *Hepatol. Int.* **2020**, *14*, 1057–1074. [CrossRef]

315. Niu, Q.; Wang, T.; Wang, Z.; Wang, F.; Huang, D.; Sun, H.; Liu, H. Adipose-Derived Mesenchymal Stem Cell-Secreted Extracellular Vesicles Alleviate Non-Alcoholic Fatty Liver Disease via Delivering MiR-223-3p. *Adipocyte* **2022**, *11*, 572–587. [CrossRef]

316. He, S.; Guo, W.; Deng, F.; Chen, K.; Jiang, Y.; Dong, M.; Peng, L.; Chen, X. Targeted Delivery of MicroRNA 146b Mimic to Hepatocytes by Lactosylated PDMAEMA Nanoparticles for the Treatment of NAFLD. *Artif. Cells Nanomed. Biotechnol.* **2018**, *46*, 217–228. [CrossRef]

317. Wang, Z.; Zhao, K.; Zhang, Y.; Duan, X.; Zhao, Y. Anti-GPC3 Antibody Tagged Cationic Switchable Lipid-Based Nanoparticles for the Co-Delivery of Anti-MiRNA27a And Sorafenib in Liver Cancers. *Pharm. Res.* **2019**, *36*, 145. [CrossRef]

318. Wu, J.; Huang, J.; Kuang, S.; Chen, J.; Li, X.; Chen, B.; Wang, J.; Cheng, D.; Shuai, X. Synergistic MicroRNA Therapy in Liver Fibrotic Rat Using MRI-Visible Nanocarrier Targeting Hepatic Stellate Cells. *Adv. Sci. Weinh. Baden-Wurtt. Ger.* **2019**, *6*, 1801809. [CrossRef]

319. El-Mezayen, N.S.; El-Hadidy, W.F.; El-Refaie, W.M.; Shalaby, T.I.; Khattab, M.M.; El-Khatib, A.S. Hepatic Stellate Cell-Targeted Imatinib Nanomedicine versus Conventional Imatinib: A Novel Strategy with Potent Efficacy in Experimental Liver Fibrosis. *J. Control. Release Off. J. Control. Release Soc.* **2017**, *266*, 226–237. [CrossRef] [PubMed]

320. Liu, Z.; Niu, D.; Zhang, J.; Zhang, W.; Yao, Y.; Li, P.; Gong, J. Amphiphilic Core-Shell Nanoparticles Containing Dense Polyethyleneimine Shells for Efficient Delivery of MicroRNA to Kupffer Cells. *Int. J. Nanomed.* **2016**, *11*, 2785–2797. [CrossRef] [PubMed]

321. Gerlach, L.O.; Skerlj, R.T.; Bridger, G.J.; Schwartz, T.W. Molecular Interactions of Cyclam and Bicyclam Non-Peptide Antagonists with the CXCR4 Chemokine Receptor. *J. Biol. Chem.* **2001**, *276*, 14153–14160. [CrossRef] [PubMed]
297. Wang, X.; Yu, B.; Ren, W.; Mo, X.; Zhou, C.; He, H.; Jia, H.; Wang, L.; Jacob, S.T.; Lee, R.J.; et al. Enhanced Hepatic Delivery of SiRNA and MicroRNA Using Oleic Acid Based Lipid Nanoparticle Formulations. *J. Control. Release Off. J. Control. Release Soc.* **2013**, *172*, 690–698. [CrossRef] [PubMed]

298. Ellipilli, S.; Wang, H.; Binzel, D.W.; Shu, D.; Guo, P. Ligand-Displaying-Exosomes Using RNA Nanotechnology for Targeted Delivery of Multi-Specific Drugs for Liver Cancer Regression. *Nanomed. Nanotechnol. Biol. Med.* **2023**, *50*, 102667. [CrossRef] [PubMed]

299. Gu, L.; Zhang, F.; Wu, J.; Zhuge, Y. Nanotechnology in Drug Delivery for Liver Fibrosis. *Front. Mol. Biosci.* **2021**, *8*, 804396. [CrossRef]

300. Kim, A.; Saikia, P.; Nagy, L.E. MiRNAs Involved in M1/M2 Hyperpolarization Are Clustered and Coordinately Expressed in Alcoholic Hepatitis. *Front. Immunol.* **2019**, *10*, 1295. [CrossRef]

301. Zeng, T.; Zhang, C.-L.; Xiao, M.; Yang, R.; Xie, K.-Q. Critical Roles of Kupffer Cells in the Pathogenesis of Alcoholic Liver Disease: From Basic Science to Clinical Trials. *Front. Immunol.* **2016**, *7*, 538. [CrossRef]

302. Hong, D.S.; Kang, Y.-K.; Borad, M.; Sachdev, J.; Ejadi, S.; Lim, H.Y.; Brenner, A.J.; Park, K.; Lee, J.-L.; Kim, T.-Y.; et al. Phase 1 Study of MRX34, a Liposomal MiR-34a Mimic, in Patients with Advanced Solid Tumours. *Br. J. Cancer* **2020**, *122*, 1630–1637. [CrossRef]

303. Cheng, S.-H.; Li, F.-C.; Souris, J.S.; Yang, C.-S.; Tseng, F.-G.; Lee, H.-S.; Chen, C.-T.; Dong, C.-Y.; Lo, L.-W. Visualizing Dynamics of Sub-Hepatic Distribution of Nanoparticles Using Intravital Multiphoton Fluorescence Microscopy. *ACS Nano* **2012**, *6*, 4122–4131. [CrossRef]

304. Shilpi, S. Drug Targeting Strategies for Liver Cancer and Other Liver Diseases. *MOJ Drug Des. Dev. Ther.* **2018**, *2*, 171–177. [CrossRef]

305. Hanna, J.; Hossain, G.S.; Kocerha, J. The Potential for MicroRNA Therapeutics and Clinical Research. *Front. Genet.* **2019**, *10*, 478. [CrossRef] [PubMed]

306. Chakraborty, C.; Sharma, A.R.; Sharma, G.; Lee, S.-S. Therapeutic Advances of MiRNAs: A Preclinical and Clinical Update. *J. Adv. Res.* **2021**, *28*, 127–138. [CrossRef] [PubMed]

307. Iacomino, G. MiRNAs: The Road from Bench to Bedside. *Genes* **2023**, *14*, 314. [CrossRef]

308. Roberts, T.C.; Langer, R.; Wood, M.J.A. Advances in Oligonucleotide Drug Delivery. *Nat. Rev. Drug Discov.* **2020**, *19*, 673–694. [CrossRef]

309. Kim, T.; Croce, C.M. MicroRNA: Trends in Clinical Trials of Cancer Diagnosis and Therapy Strategies. *Exp. Mol. Med.* **2023**, *55*, 1314–1321. [CrossRef]

310. Chakraborty, C.; Sharma, A.R.; Sharma, G.; Doss, C.G.P.; Lee, S.-S. Therapeutic MiRNA and SiRNA: Moving from Bench to Clinic as Next Generation Medicine. *Mol. Ther. Nucleic Acids* **2017**, *8*, 132–143. [CrossRef]

311. Hsu, S.-H.; Yu, B.; Wang, X.; Lu, Y.; Schmidt, C.R.; Lee, R.J.; Lee, L.J.; Jacob, S.T.; Ghoshal, K. Cationic Lipid Nanoparticles for Therapeutic Delivery of SiRNA and MiRNA to Murine Liver Tumor. *Nanomed. Nanotechnol. Biol. Med.* **2013**, *9*, 1169–1180. [CrossRef]

312. Yang, C.; Yin, M.; Xu, G.; Lin, W.-J.; Chen, J.; Zhang, Y.; Feng, T.; Huang, P.; Chen, C.-K.; Yong, K.-T. Biodegradable Polymers as a Noncoding MiRNA Nanocarrier for Multiple Targeting Therapy of Human Hepatocellular Carcinoma. *Adv. Healthc. Mater.* **2019**, *8*, e1801318. [CrossRef]

313. Ning, Q.; Liu, Y.-F.; Ye, P.-J.; Gao, P.; Li, Z.-P.; Tang, S.-Y.; He, D.-X.; Tang, S.-S.; Wei, H.; Yu, C.-Y. Delivery of Liver-Specific MiRNA-122 Using a Targeted Macromolecular Prodrug toward Synergistic Therapy for Hepatocellular Carcinoma. *ACS Appl. Mater. Interfaces* **2019**, *11*, 10578–10588. [CrossRef]

314. Li, Y.; Luan, Y.; Li, J.; Song, H.; Li, Y.; Qi, H.; Sun, B.; Zhang, P.; Wu, X.; Liu, X.; et al. Exosomal MiR-199a-5p Promotes Hepatic Lipid Accumulation by Modulating MST1 Expression and Fatty Acid Metabolism. *Hepatol. Int.* **2020**, *14*, 1057–1074. [CrossRef]

315. Niu, Q.; Wang, T.; Wang, Z.; Wang, F.; Huang, D.; Sun, H.; Liu, H. Adipose-Derived Mesenchymal Stem Cell-Secreted Extracellular Vesicles Alleviate Non-Alcoholic Fatty Liver Disease via Delivering MiR-223-3p. *Adipocyte* **2022**, *11*, 572–587. [CrossRef]

316. He, S.; Guo, W.; Deng, F.; Chen, K.; Jiang, Y.; Dong, M.; Peng, L.; Chen, X. Targeted Delivery of MicroRNA 146b Mimic to Hepatocytes by Lactosylated PDMAEMA Nanoparticles for the Treatment of NAFLD. *Artif. Cells Nanomed. Biotechnol.* **2018**, *46*, 217–228. [CrossRef]

317. Wang, Z.; Zhao, K.; Zhang, Y.; Duan, X.; Zhao, Y. Anti-GPC3 Antibody Tagged Cationic Switchable Lipid-Based Nanoparticles for the Co-Delivery of Anti-MiRNA27a And Sorafenib in Liver Cancers. *Pharm. Res.* **2019**, *36*, 145. [CrossRef]

318. Wu, J.; Huang, J.; Kuang, S.; Chen, J.; Li, X.; Chen, B.; Wang, J.; Cheng, D.; Shuai, X. Synergistic MicroRNA Therapy in Liver Fibrotic Rat Using MRI-Visible Nanocarrier Targeting Hepatic Stellate Cells. *Adv. Sci. Weinh. Baden-Wurtt. Ger.* **2019**, *6*, 1801809. [CrossRef]

319. El-Mezayen, N.S.; El-Hadidy, W.F.; El-Refaie, W.M.; Shalaby, T.I.; Khattab, M.M.; El-Khatib, A.S. Hepatic Stellate Cell-Targeted Imatinib Nanomedicine versus Conventional Imatinib: A Novel Strategy with Potent Efficacy in Experimental Liver Fibrosis. *J. Control. Release Off. J. Control. Release Soc.* **2017**, *266*, 226–237. [CrossRef] [PubMed]

320. Liu, Z.; Niu, D.; Zhang, J.; Zhang, W.; Yao, Y.; Li, P.; Gong, J. Amphiphilic Core-Shell Nanoparticles Containing Dense Polyethyleneimine Shells for Efficient Delivery of MicroRNA to Kupffer Cells. *Int. J. Nanomed.* **2016**, *11*, 2785–2797. [CrossRef] [PubMed]

321. Gerlach, L.O.; Skerlj, R.T.; Bridger, G.J.; Schwartz, T.W. Molecular Interactions of Cyclam and Bicyclam Non-Peptide Antagonists with the CXCR4 Chemokine Receptor. *J. Biol. Chem.* **2001**, *276*, 14153–14160. [CrossRef] [PubMed]
322. Zhang, C.; Hang, Y.; Tang, W.; Sil, D.; Jensen-Smith, H.C.; Bennett, R.G.; McVicker, B.L.; Oupický, D. Dually Active Polycation/MiRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease. *Pharmaceutics* **2022**, *14*, 669. [CrossRef] [PubMed]

323. Jia, H.; Ding, L.; Yu, A.; Tang, W.; Tang, S.; Zhang, C.; Oupický, D. A Boronate-Based Modular Assembly Nanosystem to Block the Undesirable Crosstalk between Hepatic Stellate Cells and Kupffer Cells. *Bioact. Mater.* **2023**, *25*, 569–579. [CrossRef] [PubMed]

324. Johnson, L.T.; Zhang, D.; Zhou, K.; Lee, S.M.; Liu, S.; Dilliard, S.A.; Farbiak, L.; Chatterjee, S.; Lin, Y.-H.; Siegwart, D.J. Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model. *Mol. Pharm.* **2022**, *19*, 3973–3986. [CrossRef] [PubMed]

325. Vaschetto, L.M. MiRNA Activation Is an Endogenous Gene Expression Pathway. *RNA Biol.* **2018**, *15*, 826–828. [CrossRef] [PubMed]

326. Xiang, H.; Tu, B.; Luo, M.; Hou, P.; Wang, J.; Zhang, R.; Wu, L. Knockdown of UCA1 Attenuated the Progression of Alcoholic Fatty Disease by Sponging MiR-214. *Mamm. Genome Off. J. Int. Mamm. Genome Soc.* **2022**, *33*, 534–542. [CrossRef] [PubMed]

327. Cho, C.J.; Myung, S.-J.; Chang, S. ADAR1 and MicroRNA; A Hidden Crosstalk in Cancer. *Int. J. Mol. Sci.* **2017**, *18*, 799. [CrossRef]

328. Tomaselli, S.; Bonamassa, B.; Alisi, A.; Nobili, V.; Locatelli, F.; Gallo, A. ADAR Enzyme and MiRNA Story: A Nucleotide That Can Make the Difference. *Int. J. Mol. Sci.* **2013**, *14*, 22796–22816. [CrossRef]

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
322. Zhang, C.; Hang, Y.; Tang, W.; Sil, D.; Jensen-Smith, H.C.; Bennett, R.G.; McVicker, B.L.; Oupický, D. Dually Active Polycation/MiRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease. *Pharmaceutics* **2022**, *14*, 669. [CrossRef] [PubMed]

323. Jia, H.; Ding, L.; Yu, A.; Tang, W.; Tang, S.; Zhang, C.; Oupický, D. A Boronate-Based Modular Assembly Nanosystem to Block the Undesirable Crosstalk between Hepatic Stellate Cells and Kupffer Cells. *Bioact. Mater.* **2023**, *25*, 569–579. [CrossRef] [PubMed]

324. Johnson, L.T.; Zhang, D.; Zhou, K.; Lee, S.M.; Liu, S.; Dilliard, S.A.; Farbiak, L.; Chatterjee, S.; Lin, Y.-H.; Siegwart, D.J. Lipid Nanoparticle (LNP) Chemistry Can Endow Unique In Vivo RNA Delivery Fates within the Liver That Alter Therapeutic Outcomes in a Cancer Model. *Mol. Pharm.* **2022**, *19*, 3973–3986. [CrossRef] [PubMed]

325. Vaschetto, L.M. MiRNA Activation Is an Endogenous Gene Expression Pathway. *RNA Biol.* **2018**, *15*, 826–828. [CrossRef] [PubMed]

326. Xiang, H.; Tu, B.; Luo, M.; Hou, P.; Wang, J.; Zhang, R.; Wu, L. Knockdown of UCA1 Attenuated the Progression of Alcoholic Fatty Disease by Sponging MiR-214. *Mamm. Genome Off. J. Int. Mamm. Genome Soc.* **2022**, *33*, 534–542. [CrossRef] [PubMed]

327. Cho, C.J.; Myung, S.-J.; Chang, S. ADAR1 and MicroRNA; A Hidden Crosstalk in Cancer. *Int. J. Mol. Sci.* **2017**, *18*, 799. [CrossRef]

328. Tomaselli, S.; Bonamassa, B.; Alisi, A.; Nobili, V.; Locatelli, F.; Gallo, A. ADAR Enzyme and MiRNA Story: A Nucleotide That Can Make the Difference. *Int. J. Mol. Sci.* **2013**, *14*, 22796–22816. [CrossRef]

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.