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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>Liver fibrosis is a severe complication of diverse chronic liver diseases characterized by a dysregulated hepatic microenvironment, and effective clinical therapeutic strategies for this condition remain lacking to date. Chimeric antigen receptor macrophages (CAR-Ms) hold considerable therapeutic potential for liver fibrosis via antigen-specific recognition and efferocytotic activity, yet their clinical translation is largely hindered by the sophisticated ex vivo preparation procedures. Herein, we report an in situ CAR-M engineering strategy that uses a phosphatidylserine (PS)\u2013incorporated, macrophage-targeted lipid nanoparticle (LNP) for the codelivery of CAR messenger RNA (mRNA) and Cas9 mRNA in vivo. Our findings demonstrate that this engineered LNP achieves efficient targeting of liver-resident macrophages. Transfection with fibroblast activation protein \u03b1 (FAP\u03b1)\u2013CAR mRNA equips macrophages with the capacity to specifically target activated hepatic stellate cells (aHSCs), whereas Cas9-mediated follistatin-like protein 1 (FSTL-1) gene editing enhances the efferocytotic function of macrophages in liver tissues. Consequently, functional CAR-Ms are generated in situ, which elicits robust antifibrotic effects, including reduced collagen deposition, restored sinusoidal architecture and enhanced immune-mediated antifibrotic activity. Collectively, our customized LNP-mediated in situ engineering of liver macrophages into CAR-Ms enables precise antifibrotic intervention for liver fibrosis and circumvents the cumbersome ex vivo CAR-M preparation process.<\/jats:p>","DOI":"10.1126\/sciadv.aeh6590","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:58:42Z","timestamp":1792778322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["In situ CAR-M engineered by liposomal mRNA nanomedicine remodels fibrotic microenvironment for ameliorating liver fibrosis"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1184-4279","authenticated-orcid":true,"given":"Hong","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, 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