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Here, we developed a fibroblast activation protein inhibitor (FAPi)\u2010modified LNP encapsulating heat shock protein 47 (HSP47) siRNA (FAPi\u2010LNP\/siHSP47) to target activated HSCs. FAPi\u2010LNP\/siHSP47 exhibited enhanced HSC targeting, efficient HSP47 silencing, reduced alpha\u2010smooth muscle actin (\u03b1\u2010SMA) expression, and marked attenuation of collagen deposition in vivo. Pharmacokinetic and protein corona analyses revealed that DSPE\u2010PEG\u2010based LNPs displayed prolonged circulation and increased area under the curve (AUC) compared with DMG\u2010PEG formulations, while FAPi modification further enhanced AUC and reduced adsorption of complement protein C3 and apolipoprotein E (ApoE), thereby decreasing hepatocyte uptake. Importantly, acute toxicity evaluation demonstrated favorable in vivo biocompatibility without hematological, inflammatory, or histopathological abnormalities. Collectively, FAPi modification enabled LNPs to specifically target activated HSCs, providing a safe and effective treatment for liver fibrosis and presenting a new strategy for directing LNPs to cells beyond hepatocytes.<\/jats:p>","DOI":"10.1002\/smll.75839","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:32:06Z","timestamp":1789655526000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FAPi\u2010Mediated siRNA Lipid Nanoparticles for the Treatment of Liver Fibrosis"],"prefix":"10.1002","author":[{"given":"Rulan","family":"Feng","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development Shanghai Frontiers Science Center of Molecular Intelligent Syntheses School of Chemistry and Molecular Engineering East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulei","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Pharmacy East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Yao","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development Shanghai Frontiers Science Center of Molecular Intelligent Syntheses School of Chemistry and Molecular Engineering East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development Shanghai Frontiers Science Center of Molecular Intelligent Syntheses School of Chemistry and Molecular Engineering East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development Shanghai Frontiers Science Center of Molecular Intelligent Syntheses School of Chemistry and Molecular Engineering East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmacy East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Pharmacy East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-3122","authenticated-orcid":false,"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers &amp; Key Laboratory of Smart Drug Delivery Ministry of Education &amp; Department of Pharmacy Shanghai Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5215-2829","authenticated-orcid":false,"given":"Changyou","family":"Zhan","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers &amp; Key Laboratory of Smart Drug Delivery Ministry of Education &amp; Department of Pharmacy Shanghai Fudan University  Shanghai People's Republic of China"},{"name":"Department of Pharmacology School of Basic Medical Sciences &amp; State Key Laboratory of Molecular Engineering of Polymers Fudan University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering and Technology Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development Shanghai Frontiers Science Center of Molecular Intelligent Syntheses School of Chemistry and Molecular Engineering East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy East China Normal University  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7036-1517","authenticated-orcid":false,"given":"Kuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology School of Basic Medical Sciences &amp; 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