IL‐21 Loading CaMnCO3 Vitality Backpacks Boost CAR‐T Cell Synergistic Immunotherapy

Abstract Chimeric antigen receptor (CAR)‐T‐cell therapy achieves considerable success in the treatment of malignant tumors, but clinical relapse due to the tumor microenvironment (TME) is very common. The TME of solid tumors is characterized by weak acidity, hypoxia, and elevated reactive oxygen species (ROS) levels, which collectively impair the function and persistence of infiltrating CAR‐T cells. In this study, acid‐sensitive responsive CaMnCO 3 nanoparticles (CMC NPs), are developed that simultaneously mitigate TME acidosis and hypoxia. IL‐21 is encapsulated within CMC NPs (denoted as CMC‐21), which are then surface‐conjugated to CAR‐T cells as functional ‘vitality backpacks’ to enhance cellular activity. The CMC‐21 backpack enables sustained release of IL‐21, persistently enhancing CAR‐T cell antitumor immunity across both low‐ and high‐dose infusion regimens. Furthermore, CMC NPs exert dual modulatory effects on the TME by: 1) consuming protons to neutralize acidic conditions, and 2) catalytically converting endogenous H 2 O 2 to O 2 to relieve hypoxia. This multimodal remodeling of the immunosuppressive TME significantly enhances the infiltration and activity of adoptively transferred CAR‐T cells while simultaneously boosting endogenous T cell and NK cell recruitment in vivo. These findings establish a novel CAR‐T cell enhancement strategy through sustained IL‐21 release from CMC‐21 backpacks, offering new possibilities for solid tumor immunotherapy.