Lipid nanoparticles produce chimeric antigen receptor macrophages (CAR-M) in situ for the treatment of solid tumors

Abstract

Chimeric antigen receptor-macrophage (CAR-M) therapy has shown significant promise for solid tumor treatment. However, its clinical implementation faces challenges due to the intricate ex vivo manufacture procedures involved. Given that the nano drug delivery system (NDDS) is readily taken up by macrophages in vivo, we here propose a convenient approach for in situ CAR-M generation. We first developed lipid nanoparticles loaded with Trop2-CAR plasmid DNA (LNP/CAR Trop2). In vivo experiments showed that LNP/CAR Trop2 could transfect macrophages and produce CAR-M following either intravenous or intratumoral injection. Notably, the majority of CAR-M displayed an M1 phenotype, resulting in the selective elimination of Trop2-overexpressing tumor cells and a reduction in tumor volume in tumor-bearing mice. Furthermore, the produced CAR-M in situ promoted the proliferation of NK cells and CD8 + T cells, further augmenting their anti-tumor effect. This strategy transforms the inherent disadvantage of NDDSs being easily taken up by macrophages into an advantage, enabling the generation of CAR-M in situ and circumventing the complex preparation process ex vivo. This study will improve the convenience and practicality of clinical use of CAR-M and provide a new approach for solid tumors therapy.