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Traditional chemical drugs that have proven effective at treating other types of tissue fibrosis may be repurposed for treating liver fibrosis but face inefficient outcomes or elicit undesirable side effects. Hepatic\u2010targeted drug nanocarriers offer a potential strategy for achieving localized drug release to effectively alleviate liver fibrosis while mitigating off\u2010target effects. Elevated levels of fibroblast activation protein\u2010\u03b1 (FAP\u2010\u03b1) have been associated with liver fibrosis and the presence of platelet\u2010derived growth\u2010factor\u2010receptor\u2010\u03b2\u2010overexpressing activated hepatic stellate cells. Therefore, FAP\u2010\u03b1\u2010responsive nanoshells are developed from hepatic fibrosis targeting peptides to protect and transport pirfenidone (PFD) to fibrotic livers for potentiated therapeutic efficacy. In vitro experiments validate that PFD\u2010loaded hepatic\u2010 and fibrosis\u2010targeting nanoshells (PFD@ns) lessen transforming\u2010growth\u2010factor\u2010\u03b21\u2010driven collagen production and activation of hepatic stellate cells. In animal models of liver fibrosis, PFD@ns increase the efficacy of PFD in preventing fibrosis, alleviating proinflammatory cell infiltration, and modulating the PI3K\/AKT\/mTOR signaling pathway. In conclusion, these findings suggest that the hepatic\u2010 and fibrosis\u2010targeted PFD@ns can potentially serve as an effective tool in the treatment of liver fibrosis.<\/jats:p>","DOI":"10.1002\/adhm.202500101","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:17:00Z","timestamp":1748333820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Tissue\u2010Microenvironment\u2010Responsive Self\u2010Assembling Peptide Nanoshells Boost Pirfenidone Efficacy in the Treatment of Liver Fibrosis"],"prefix":"10.1002","volume":"14","author":[{"given":"Ruifang","family":"Li","sequence":"first","affiliation":[{"name":"School of Medicine Nankai University  Tianjin 300071 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