REFERENCES
1. Kostallari E, Schwabe RF, Guillot A. Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells. Cell Mol Immunol. 2025;22:1205-25.
2. Karlsen TH, Lammert F, Thompson RJ. Genetics of liver disease: from pathophysiology to clinical practice. J Hepatol. 2015;62:S6-S14.
3. Mücke MM, Fong S, Foster GR, Lillicrap D, Miesbach W, Zeuzem S. Adeno-associated viruses for gene therapy - clinical implications and liver-related complications, a guide for hepatologists. J Hepatol. 2024;80:352-61.
4. Pierce GF, Fong S, Long BR, Kaczmarek R. Deciphering conundrums of adeno-associated virus liver-directed gene therapy: focus on hemophilia. J Thromb Haemost. 2024;22:1263-89.
5. Hussain MS, Maqbool M, Arab MM, et al. Transforming hemophilia management: lessons from gene therapy clinical trials. Mol Biotechnol. 2025;68:1597-608.
6. Bhadury R, Athar M, Mishra P, Gogoi C, Sharma S, Ghorpade DS. Development and validation of AAV-mediated liver, liver-VAT, and liver-brain SORT and therapeutic regulation of FASN in hepatic de novo lipogenesis. Cells. 2025;14:372.
7. Zakas PM, Cunningham SC, Doherty A, et al. Sleeping beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency. Mol Ther. 2024;32:3356-71.
8. Herrera-Barrera M, Gautam M, Lokras A, Vlasova K, Foged C, Sahay G. Lipid nanoparticle-enabled intracellular delivery of prime editors. AAPS J. 2023;25:65.
9. Rothgangl T, Tálas A, Ioannidi EI, et al. Treatment of a metabolic liver disease in mice with a transient prime editing approach. Nat Biomed Eng. 2025;9:1705-18.
10. Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, Francés R. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol. 2021;18:411-31.
11. Wang L, He L, Yi W, et al. ADAMTS18-fibronectin interaction regulates the morphology of liver sinusoidal endothelial cells. iScience. 2024;27:110273.
12. Zhou J, Wang J, Zhang L, Zhang C, Tian C. Defenestration of liver sinusoidal endothelial cells: the trigger of liver fibrosis. Pharmaceuticals. 2025;18:893.
13. Wang N, Guo M, Zhang C, et al. Liver regeneration: unraveling the molecular mechanisms and clinical application. J Transl Med. 2025;23:1409.
14. Gilgenkrantz H, Collin De L'hortet A. Understanding liver regeneration: from mechanisms to regenerative medicine. Am J Pathol. 2018;188:1316-27.
15. Li B, Rodrigo-Torres D, Pelz C, et al. Cell networks in the mouse liver during partial hepatectomy. Stem Cell Rep. 2025;20:102683.
17. Moore HF, Usmani S, Froghi S, et al. Immune cells in liver regeneration: current evidence and potential clinical targets. Int Rev Immunol. 2025;44:353-92.
18. Venzin V, Beccaria CG, Perucchini C, et al. CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming. Nat Immunol. 2025;26:1352-66.
19. Ferriero R, Bruno G, Padula A, et al. Impact of liver fibrosis on AAV-mediated gene transfer to mouse hepatocytes. Nat Commun. 2025;16:2118.
20. Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular mechanisms of liver fibrosis. Front Pharmacol. 2021;12:671640.
21. Zhou T, Kiran M, Lui KO, Ding Q. Decoding liver fibrogenesis with single-cell technologies. Life Med. 2022;1:333-44.
22. Yang T, Gu Z, Feng J, Shan J, Qian C, Zhuang N. Non-parenchymal cells: key targets for modulating chronic liver diseases. Front Immunol. 2025;16:1576739.
23. Muro AF, D’antiga L, Mingozzi F. Gene therapy in pediatric liver disease. In: D'antiga L, editors. Pediatric hepatology and liver transplantation. Cham: Springer International Publishing; 2019. pp. 799-829.
24. Simini G, Batty P. The hepatic Odyssey of Adeno-associated virus: from gene delivery to long-term outcomes. J Thromb Haemost. 2025;23:3781-90.
25. Dalwadi DA, Calabria A, Tiyaboonchai A, et al. AAV integration in human hepatocytes. Mol Ther. 2021;29:2898-909.
26. Jeyaraj R, Brown LK, Jagadisan B, et al. Safety of in vivo gene therapy in children: mechanisms and management of liver injury. Lancet Child Adolesc Health. 2026;10:448-61.
27. Byrne BJ, Flanigan KM, Matesanz SE, et al. Current clinical applications of AAV-mediated gene therapy. Mol Ther. 2025;33:2479-516.
28. Baruteau J, Cunningham SC, Yilmaz BS, et al. Safety and efficacy of an engineered hepatotropic AAV gene therapy for ornithine transcarbamylase deficiency in cynomolgus monkeys. Mol Ther Methods Clin Dev. 2021;23:135-46.
29. Shi X, Aronson SJ, Ten Bloemendaal L, et al. Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients. Mol Ther Methods Clin Dev. 2021;20:287-97.
30. Elmore ZC, Oh DK, Simon KE, Fanous MM, Asokan A. Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme. JCI Insight. 2020;5:e139881.
31. Schulz M, Levy DI, Petropoulos CJ, et al. Binding and neutralizing anti-AAV antibodies: detection and implications for rAAV-mediated gene therapy. Mol Ther. 2023;31:616-30.
32. Dhungel BP, Winburn I, Pereira CDF, Huang K, Chhabra A, Rasko JEJ. Understanding AAV vector immunogenicity: from particle to patient. Theranostics. 2024;14:1260-88.
33. Jagadisan B, Dhawan A. Hepatotoxicity in adeno-associated viral vector gene therapy. Curr Hepatol Rep. 2023;22:276-90.
34. Kaiser CW, Rouchka EC, Smith ML. Adaptation of lentiviral vectors for viral gene therapy and their impact on host cell biology. J Transl Med. 2026;24:272.
35. Ranzani M, Cesana D, Bartholomae CC, et al. Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer. Nat Methods. 2013;10:155-61.
36. Cesana D, Ranzani M, Volpin M, et al. Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo. Mol Ther. 2014;22:774-85.
37. Baek Y, Seo YR, Kim S, Jung S, Kim CH, Lee Y. From ex vivo to in vivo: advances in lentiviral vector engineering for CAR-T therapy. Immune Netw. 2026;26:e13.
38. Kang DD, Marks A, Morla-Folch J, Dong Y, Brown BD, Teunissen AJP. Targeting and tracking mRNA lipid nanoparticles at the particle, transcript and protein level. Nat Biomed Eng. 2025;9:1591-609.
39. Hosseini-Kharat M, Bremmell KE, Prestidge CA. Why do lipid nanoparticles target the liver? Understanding of biodistribution and liver-specific tropism. Mol Ther Methods Clin Dev. 2025;33:101436.
40. Qiu M, Glass Z, Chen J, et al. Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proc Natl Acad Sci USA. 2021;118:e2020401118.
41. Zhang T, Yin H, Li Y, et al. Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo. iScience. 2024;27:109804.
42. Younis MA, Sato Y, Elewa YH, Kon Y, Harashima H. Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis. J Controlled Release. 2023;353:685-98.
43. Kim Y, Chatterjee S, Robertson AL, et al. Mannose-conjugated cholesterol containing lipid nanoparticles for active targeted mRNA delivery to liver sinusoidal endothelial and kupffer cells. Bioconjugate Chem. 2025;36:2181-96.
44. Kasiewicz LN, Biswas S, Beach A, et al. GalNAc-lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy. Nat Commun. 2023;14:2776.
45. Elsharkasy OM, Nordin JZ, Hagey DW, et al. Extracellular vesicles as drug delivery systems: why and how? Adv Drug Delivery Rev. 2020;159:332-43.
46. Serrano DR, Juste F, Anaya BJ, et al. Exosome-based drug delivery: a next-generation platform for cancer, infection, neurological and immunological diseases, gene therapy and regenerative medicine. Pharmaceutics. 2025;17:1336.
47. Sun X, Lian Y, Tian T, Cui Z. Virus-like particle encapsulation of functional proteins: advances and applications. Theranostics. 2024;14:7604-22.
48. Zhang J, Yang X, Chang Z, Zhu W, Ma Y, He H. Polymeric nanocarriers for therapeutic gene delivery. Asian J Pharm Sci. 2025;20:101015.
49. Cavazza A, Molina-Estévez FJ, Reyes ÁP, et al. Advanced delivery systems for gene editing: a comprehensive review from the GenE-HumDi COST Action Working Group. Mol Ther Nucl Acids. 2025;36:102457.
50. Canepari C, Milani M, Simoni C, et al. Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes. Nat Commun. 2025;16:4802.
51. Simoni C, Nozi J, Starinieri F, et al. Liver fibrosis negatively impacts in vivo gene transfer to murine hepatocytes. Nat Commun. 2025;16:2119.
52. Wang J, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Sig Transduct Target Ther. 2024;9:78.
53. D’antiga L, Beuers U, Ronzitti G, et al. Gene therapy in patients with the crigler-najjar syndrome. N Engl J Med. 2023;389:620-31.
54. Schambach A, Buchholz CJ, Torres-Ruiz R, et al. A new age of precision gene therapy. Lancet. 2024;403:568-82.
55. Ay C, Reinisch A. Gene therapy: principles, challenges and use in clinical practice. Wien Klin Wochenschr. 2024;137:261-71.
56. Sayed N, Allawadhi P, Khurana A, et al. Gene therapy: comprehensive overview and therapeutic applications. Life Sci. 2022;294:120375.
57. Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36:765-71.
58. Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24:927-30.
59. Xu W, Zhang S, Qin H, Yao K. From bench to bedside: cutting-edge applications of base editing and prime editing in precision medicine. J Transl Med. 2024;22:1133.
60. Murray JB, Harrison PT, Scholefield J. Prime editing: therapeutic advances and mechanistic insights. Gene Ther. 2024;32:83-92.
61. Simoni C, Barbon E, Muro AF, Cantore A. In vivo liver targeted genome editing as therapeutic approach: progresses and challenges. Front Genome Ed. 2024;6:1458037.
62. Whittaker MN, Testa LC, Quigley A, et al. Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs. Nat Biomed Eng. 2025:1545.
63. Khirallah J, Bloomer H, Wich D, et al. In vivo base editing of Angptl3 via lipid nanoparticles to treat cardiovascular disease. Mol Ther Nucl Acids. 2025;36:102486.
64. Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021;385:493-502.
65. Liu D, Cao D, Han R. Recent advances in therapeutic gene-editing technologies. Mol Ther. 2025;33:2619-44.
66. Xiong H, Guo J. Targeting hepatic stellate cells for the prevention and treatment of liver cirrhosis and hepatocellular carcinoma: strategies and clinical translation. Pharmaceuticals. 2025;18:507.
67. Martínez-García J, Molina A, González-Aseguinolaza G, Weber ND, Smerdou C. Gene therapy for acquired and genetic cholestasis. Biomedicines. 2022;10:1238.
68. Yang AY, Wistuba-Hamprecht K, Greten TF, Ruf B. Innate-like T cells in liver disease. Trends Immunol. 2024;45:535-48.
69. De Sabbata G, Boisgerault F, Guarnaccia C, et al. Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector. Mol Ther Methods Clin Dev. 2021;20:169-80.
70. Seker Yilmaz B, Gissen P. Genetic therapy approaches for ornithine transcarbamylase deficiency. Biomedicines. 2023;11:2227.
71. Weiss JN. Ornithine transcarbamylase deficiency. In: Neurologic gene therapy. Cham: Springer Nature Switzerland; 2025. pp. 421-9.
72. Sambati V, Laudisio S, Motta M, Esposito S. Therapeutic options for crigler-najjar syndrome: a scoping review. Int J Mol Sci. 2024;25:11006.
73. Kishnani PS, Sun B, Koeberl DD. Gene therapy for glycogen storage diseases. Hum Mol Genet. 2019;28:R31-41.
74. Chou JY, Mansfield BC. Gene therapy and genome editing for type I glycogen storage diseases. Front Mol Med. 2023;3:1167091.
75. Moreno D, Murillo O, Gazquez C, et al. Visualization of the therapeutic efficacy of a gene correction approach in Wilson’s disease by laser-ablation inductively coupled mass spectrometry. J Hepatol. 2018;68:1088-90.
76. Zeng C, Lin Y, Lu X, et al. Evaluation of efficacy and safety of AAV8-ΔC4ATP7B gene therapy in a mutant mouse model of Wilson’s disease. Mol Ther Methods Clin Dev. 2025;33:101435.
77. Bosma PJ, Wits M, Oude-Elferink RPJ. Gene therapy for progressive familial intrahepatic cholestasis: current progress and future prospects. Int J Mol Sci. 2020;22:273.
78. Weber ND, Odriozola L, Martínez-García J, et al. Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model. Nat Commun. 2019;10:5694.
79. Ermi AG, Younis RM, Rodriguez K, Sarkar D. Gene therapy strategies for hepatocellular carcinoma (HCC): current landscape and future directions. Cancers. 2025;17:3608.
80. Zhang J, Xiao Y, Zhang J, Yang Y, Zhang L, Liang F. Recent advances of engineered oncolytic viruses-based combination therapy for liver cancer. J Transl Med. 2024;22:3.
81. Shen Y, Bai X, Zhang Q, et al. Oncolytic virus VG161 in refractory hepatocellular carcinoma. Nature. 2025;641:E5.
82. Zhou Y, Wei S, Xu M, et al. CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges. Front Immunol. 2024;15:1489649.
83. Hong J, Yu J, Buratto D, et al. Unveiling the role of mechanical microenvironment in hepatocellular carcinoma: molecular mechanisms and implications for therapeutic strategies. Int J Biol Sci. 2024;20:5239-53.
84. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357-65.
85. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215-27.
86. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020;382:29-40.
87. Lim J, Choi SJ, Gao F, Kishnani PS, Sun B. A novel gene therapy approach for GSD III using an AAV vector encoding a bacterial glycogen debranching enzyme. Mol Ther Methods Clin Dev. 2020;18:240-9.
88. Chandler RJ, Di Pasquale G, Sloan JL, et al. Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9. Mol Ther Methods Clin Dev. 2022;27:61-72.
89. Chandler RJ, Di Pasquale G, Choi E, et al. Systemic gene therapy using an AAV44.9 vector rescues a neonatal lethal mouse model of propionic acidemia. Mol Ther Methods Clin Dev. 2023;30:181-90.
90. Brantly ML, Chulay JD, Wang L, et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci USA. 2009;106:16363-8.
91. Yao ZQ, Schank MB, Zhao J, et al. The potential of HBV cure: an overview of CRISPR-mediated HBV gene disruption. Front Genome Ed. 2024;6:1467449.
92. Hsueh Y, Chang Y, Loh C, Gershwin ME, Chuang Y. AAV-IL-22 modifies liver chemokine activity and ameliorates portal inflammation in murine autoimmune cholangitis. J Autoimmun. 2016;66:89-97.
93. Zhang VX, Tsui Y, Ng IO. MASLD/MASH—New mechanisms and treatments. Hepatol Commun. 2025;9:e0770.
94. Liu S, Ji Y, Wei L, et al. Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle. Nat Commun. 2025;16:7961.
95. Gross D, Tedesco N, Leborgne C, Ronzitti G. Overcoming the challenges imposed by humoral immunity to AAV vectors to achieve safe and efficient gene transfer in seropositive patients. Front Immunol. 2022;13:857276.
96. Bakos T, Mészáros T, Kozma GT, et al. mRNA-LNP COVID-19 vaccine lipids induce complement activation and production of proinflammatory cytokines: mechanisms, effects of complement inhibitors, and relevance to adverse reactions. Int J Mol Sci. 2024;25:3595.
97. Saxena S, Sharma S, Kumar G, Thakur S. Unravelling the complexity of CARPA: a review of emerging advancements in therapeutic strategies. Arch Dermatol Res. 2025;317:439.
98. Assaf BT. Systemic toxicity of recombinant adeno-associated virus gene therapy vectors. Toxicol Pathol. 2024;52:523-30.
100. Anzalone AV, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576:149-57.
101. Reiss UM, Davidoff AM, Tuddenham EG, et al. Sustained clinical benefit of AAV gene therapy in severe hemophilia B. N Engl J Med. 2025;392:2226-34.
102. Clément N, Grieger JC. Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol Ther Methods Clin Dev. 2016;3:16002.
103. Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021;6:1078-94.
104. Wec AZ, Lin KS, Kwasnieski JC, Sinai S, Gerold J, Kelsic ED. Overcoming immunological challenges limiting capsid-mediated gene therapy with machine learning. Front Immunol. 2021;12:674021.
105. Segers S. Heritable genome editing: ethical aspects of a developing domain. Hum Reprod. 2023;38:2055-61.
106. Iyer AA, Saade D, Bharucha-Goebel D, et al. Ethical challenges for a new generation of early-phase pediatric gene therapy trials. Genet Med. 2021;23:2057-66.
107. Yang W, Wang A, Liu B. Adeno-associated virus gene therapy for hemophilia: an update meta-analysis and systematic review. Front Med. 2025;12:1580264.
108. Barnes C, Scheideler O, Schaffer D. Engineering the AAV capsid to evade immune responses. Curr Opin Biotechnol. 2019;60:99-103.
109. Eid F, Chen AT, Chan KY, et al. Systematic multi-trait AAV capsid engineering for efficient gene delivery. Nat Commun. 2024;15:6602.
110. Gao H, Gao S, Kan G, Valentovich LN, An Y. Research progress of base editing and prime editing tools based on the CRISPR/Cas system. Mol Ther Nucleic Acids. 2025;36:102771.
111. Booth BJ, Nourreddine S, Katrekar D, et al. RNA editing: expanding the potential of RNA therapeutics. Mol Ther. 2023;31:1533-49.
112. Jin G, Lim B. Epigenome editing and epigenetic gene regulation in disease phenotypes. Korean J Chem Eng. 2022;39:1361-7.
113. Rezvani M, Español-Suñer R, Malato Y, et al. In vivo hepatic reprogramming of myofibroblasts with AAV vectors as a therapeutic strategy for liver fibrosis. Cell Stem Cell. 2016;18:809-16.
114. Jalan-Sakrikar N, Brevini T, Huebert RC, Sampaziotis F. Organoids and regenerative hepatology. Hepatology. 2023;77:305-22.
115. Adams MT, Jasper H, Mosteiro L. Unlocking regeneration: how partial reprogramming resembles tissue healing. Curr Opin Genet Dev. 2025;93:102351.
116. Hashem EM, Karrar AM, Mabrouk MS. Advancing liver cancer diagnosis and treatment with multi-omics approaches: a systematic review. Discov Onc. 2025;16:2188.
117. Lu X, Li Y, Li Y, et al. Advances of multi-omics applications in hepatic precancerous lesions and hepatocellular carcinoma: the role of extracellular vesicles. Front Mol Biosci. 2023;10:1114594.
118. Rao J, Li Y, Leng K. Artificial intelligence in hepatocellular carcinoma screening: applications and challenges. Front Med. 2026;12:1713887.
119. Malik S, Das R, Thongtan T, Thompson K, Dbouk N. AI in hepatology: revolutionizing the diagnosis and management of liver disease. J Clin Med. 2024;13:7833.
120. Joseph AM, Karas M, Ramadan Y, Joubran E, Jacobs RJ. Ethical perspectives of therapeutic human genome editing from multiple and diverse viewpoints: a scoping review. Cureus. 2022;14:e31927.
