In situ CAR-M engineered by liposomal mRNA nanomedicine remodels fibrotic microenvironment for ameliorating liver fibrosis
- 1Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
- 2Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
- 3PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China.
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.
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BibTeX
@article{xiao2026situ,
title = {{In situ CAR-M engineered by liposomal mRNA nanomedicine remodels fibrotic microenvironment for ameliorating liver fibrosis}},
author = {Hong Xiao and Xiaoxia Li and Kaimin Cai and Yifei Leng and Xiaoyan Miao and Tinghui Yin and Xintao Shuai and Jie Ren},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh6590},
url = {https://www.science.org/doi/10.1126/sciadv.aeh6590},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - In situ CAR-M engineered by liposomal mRNA nanomedicine remodels fibrotic microenvironment for ameliorating liver fibrosis
AU - Hong Xiao
AU - Xiaoxia Li
AU - Kaimin Cai
AU - Yifei Leng
AU - Xiaoyan Miao
AU - Tinghui Yin
AU - Xintao Shuai
AU - Jie Ren
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aeh6590
UR - https://www.science.org/doi/10.1126/sciadv.aeh6590
AB - 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.
SN - 2375-2548
ER -