CAR Macrophages Engineered In Vivo for Attenuating Myocardial Ischemia-Reperfusion Injury

作者：Heng Du, Xintong You, Jiahe Zhang, Siqi Liu, Yanan Zhou, Yuhan Wang, Chaofan Yang, Yanan Meng, Xu Liu, Hao Zhang, Yujing Li, Jianghua Shen, Yuan Hai-long, Pengfei Xu, Chuting He, Yi Xiao, Zeyu Gao, Jingyi Zang, Tuo Wei, Moshi Song · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.125.326716 · 被引用次数：38 · 研究领域：Cardiac Fibrosis and Remodeling、Tissue Engineering and Regenerative Medicine、Peptidase Inhibition and Analysis

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury induces myocardial fibrosis that compromises cardiac function and electrical conduction, yet current clinical options remain inadequate. To address this unmet need, we explored macrophage-targeted lipid nanoparticles (LNPs) encapsulating FAP CAR (FAP [fibroblast activation protein]-targeted chimeric antigen receptor) mRNA for in vivo generation of FAP CAR macrophages and evaluated their therapeutic potential in reducing myocardial fibrosis and improving cardiac function after myocardial I/R injury. METHODS: We formulated 1,2-dioleoyl-sn-glycero-3-phospho-l-serine-doping ALC-0315 (an ionizable lipid) LNP to deliver FAP CAR mRNA to generate FAP CAR macrophages. The platform was first validated in vitro by assessing phagocytosis of FAP-overexpressing fibroblasts by these macrophages. For in vivo evaluation, C57BL/6J mice subjected to I/R injury received intravenous administration of PBS, control LNPs, or LNP-FAP CAR (LNPs encapsulating mRNA encoding a FAP-targeting CAR). Comprehensive analyses included tracking the biodistribution of the resultant FAP CAR macrophages, quantitative measurement of fibrosis reduction, assessment of cardiac function by echocardiography, and safety evaluations. RESULTS: LNP-FAP CAR successfully generated functional FAP CAR macrophages that demonstrated phagocytosis ability toward FAP-positive fibroblasts in vitro. In vivo studies revealed that intravenous delivery of LNP-FAP CAR generated funct...