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In situ CAR-M engineered by liposomal mRNA nanomedicine remodels fibrotic microenvironment for ameliorating liver fibrosis

ABSTRACT: 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-M) 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 employs a phosphatidylserine (PS)-incorporated, macrophage-targeted lipid nanoparticle (LNP) for the co-delivery of CAR 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 α (FAPα)-CAR mRNA equips macrophages with the capacity to specifically target activated hepatic stellate cells (aHSCs), while Cas9-mediated follistatin-like protein 1 (FSTL-1) gene editing enhances the efferocytotic function of macrophages in liver tissues. Consequently, functional CAR-M 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-M enables precise antifibrotic intervention for liver fibrosis, and circumvents the cumbersome ex vivo CAR-M preparation process.

ORGANISM(S): Mus musculus

PROVIDER: GSE327385 | GEO | 2026/08/30

REPOSITORIES: GEO

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