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Current antifibrotic nanomedicines face significant limitations, including poor penetration into fibrotic tissue, rapid clearance, and suboptimal therapeutic efficacy. The dense fibrotic ECM acts as a major physiological barrier, necessitating the development of a targeted delivery strategy to achieve effective therapeutic outcomes. Methods: We designed a liposomal delivery system functionalized with the GBI-10 aptamer and encapsulating obeticholic acid (OCA lips@Apt) to enhance selective delivery to fibrotic liver tissue while minimizing systemic toxicity. Results: Both in vitro and in vivo studies demonstrated that the aptamer-modified OCA liposomes effectively treated hepatic fibrosis through dual mechanisms: modulation of abnormal bile acid metabolism and attenuation of inflammation. The targeted delivery system leveraged the overexpression of Tenascin-C (TnC), a key ECM component in fibrotic tissues, for precise localization and enhanced endocytosis via the exposed cationic liposome surface. Conclusions: The OCA lips@Apt nanodrug demonstrated superior therapeutic efficacy with minimal off-target effects, offering a promising strategy to overcome critical barriers in liver fibrosis treatment. By precisely targeting the fibrotic ECM and modulating key pathological pathways, this TnC-guided liposomal delivery system provides a significant advancement in antifibrotic nanomedicine.<\/jats:p>","DOI":"10.3390\/pharmaceutics17010032","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T12:37:19Z","timestamp":1735648639000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tenascin C-Guided Nanosystem for Precision Delivery of Obeticholic Acid in Liver Fibrosis Therapy"],"prefix":"10.3390","volume":"17","author":[{"given":"Yawen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taiyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6099-4356","authenticated-orcid":false,"given":"Hongliang","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2056-0286","authenticated-orcid":false,"given":"Lisha","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China"},{"name":"NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41573-019-0040-5","article-title":"Targeting metabolic dysregulation for fibrosis therapy","volume":"19","author":"Zhao","year":"2020","journal-title":"Nat. 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