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Persistent bile duct obstruction induces various pathological conditions, including jaundice, inflammation, and liver fibrosis; however, the exact pathogenesis of biliary atresia is not yet fully understood. Nuclear factor-\u03baB (NF-\u03baB) is widely acknowledged as a key regulator in the pathogenesis of hepatitis and liver fibrosis, and extensive research has been conducted to develop strategies to effectively inhibit its activity to mitigate liver damage. Exosome-based therapeutic platforms offer targeted NF-\u03baB inhibition with low immunogenicity and enhanced liver-specific delivery. This study aimed to evaluate the therapeutic efficacy of Exo-SrI\u03baB in treating cholestatic liver fibrosis using experimental animal models. Methods: Exo-SrI\u03baB (an exosome-based therapy containing the super-repressor I\u03baB protein) using EXPLOR technology (Exosome engineering for Protein Loading via Optically Reversible protein-protein interactions) to encapsulate the super repressor I\u03baB (SrI\u03baB) within exosomes. The therapeutic efficacy of Exo-SrI\u03baB was assessed in minipig and mouse models with experimentally induced cholestatic liver disease. Results: Administration of Exo-SrI\u03baB significantly attenuated liver fibrosis progression in both animal models by inhibiting NF-\u03baB nuclear translocation and reducing the expression of fibrotic markers. Treated animals exhibited reduced collagen deposition, lower \u03b1-SMA levels, and improved hepatic function compared to untreated controls. Conclusion: Exo-SrI\u03baB effectively suppressed NF-\u03baB signaling and alleviated liver fibrosis in experimental cholestatic liver disease models, suggesting that exosome-based therapeutics may offer a targeted and biocompatible application to managing liver fibrosis and other chronic liver diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics17020264","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T04:40:25Z","timestamp":1739767225000},"page":"264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineered Exosomes Carrying Super-Repressor I\u03baB Reduced Biliary Atresia-Induced Liver Fibrosis in Minipig and Mouse Models"],"prefix":"10.3390","volume":"17","author":[{"given":"Jisoo","family":"Kang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheolhyoung","family":"Park","sequence":"additional","affiliation":[{"name":"ILIAS Biologics Inc., Daejeon 34014, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanoul","family":"Yun","sequence":"additional","affiliation":[{"name":"ILIAS Biologics Inc., Daejeon 34014, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-9136","authenticated-orcid":false,"given":"Chulhee","family":"Choi","sequence":"additional","affiliation":[{"name":"ILIAS Biologics Inc., Daejeon 34014, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wonhyo","family":"Seo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea"},{"name":"Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Literature (2009). 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