In Situ Chimeric Antigen Receptor Macrophage Therapy via Co-Delivery of mRNA and Immunostimulant

Cancer immunotherapy employing chimeric antigen receptor (CAR) technology has achieved significant clinical success in hematologic malignancies, but faces limitations in solid tumors. Among alternative strategies, CAR-macrophage therapy offers distinct advantages in solid tumor settings. However, current ex vivo approaches are hindered by inefficient gene transfer into macrophages and challenges in maintaining an antitumor macrophage phenotype. Here, we report an in situ CAR-macrophage therapy via codelivery of mRNA and immunostimulant. By leveraging lipid nanoparticles (LNPs) designed to selectively transfect tumor-associated macrophages, we circumvent extensive ex vivo manipulation and achieve robust CAR expression directly within the tumor microenvironment. Furthermore, codelivery of a stimulator of interferon genes (STING) agonist amplifies local immune activation, leading to reinforced CAR-macrophage functionality and enhanced antitumor effects in a mouse melanoma model. This in vivo strategy addressed key obstacles of CAR-macrophage therapy in solid tumors by enabling direct cellular targeting, potent immunomodulation, and simplified manufacturing. Our findings suggest an LNP-enabled approach for CAR-macrophage immunotherapy to overcome the limitations associated with conventional CAR-T cell therapies.