Authors
Hong Xiao, Xiaoxia Li, Kaimin Cai, Yifei Leng, Xiaoyan Miao, Tinghui Yin, Xintao Shuai, Jie Ren
Published in
Science advances. Volume 12. Issue 43. Pages eaeh6590. Oct 23, 2026. Epub Oct 23, 2026.
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-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)-incorporated, 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 α (FAPα)-CAR 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.
PMID:
42913010
Bibliographic data and abstract were imported from PubMed on 24 Oct 2026.
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