Chimeric antigen receptor macrophages (CAR-Ms) therapy has shown great promise in liver fibrosis, however limited anti-inflammatory capacity of CAR-Ms in the fibrotic foci compromises their anti-fibrotic potency. We here report tripartite motif containing 13 (TRIM13) engineered CAR-Ms for effectively manipulating the anti-inflammatory phenotype of CAR-Ms, augmenting their anti-fibrosis efficacy. Specifically, our efferocytosis-sparked lipid nanoparticles (ESLNPs) efficiently engineered fibrosis-associated macrophages to anti-inflammatory CAR-Ms by co-delivering mRNA encoding TRIM13 and anti-fibroblast activation protein (FAP) CAR respectively. Our data demonstrated these reprogrammed CAR-Ms exhibited a sustained anti-inflammatory phenotype via blocking the mitochondrial DNA (mtDNA)-STING pathway through the overexpression of TRIM13, and showed notable FAP-targeted phagocytosis. Treatment with ESLNPs in male mice with liver fibrosis obviously ameliorated fibrosis through synergizing anti-fibrotic and inflammation-resolution activities, ultimately prompting substantial hepatic function restoration. In sum, our findings established that remodeling and sustaining the anti-inflammatory phenotype of CAR-Ms markedly elevated their therapeutic efficacy in liver fibrosis, benefiting CAR-Ms therapy with broad application in other fibrotic diseases.
Gao et al. (Fri,) studied this question.