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

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.