Intraparticle Double‐Scattering‐Decoded Sonogenetics for Augmenting Immune Checkpoint Blockade and CAR‐T Therapy

Abstract Genetically arming new chimeric antigen receptors (CARs) on T cells is a prevalent method to fulfill CAR‐T immunotherapy. However, this approach fails to completely address the poor infiltration, complex immunosuppressive tumor microenvironment (ITM), and insufficient immune cells, which are recognized as the three dominant hurdles to discouraging the trafficking and persistence of CAR‐T and immune checkpoint blockade (ICB) immunotherapies against solid tumors. To address the three hurdles, a sonoimmunity‐engineered nanoplatform is designed in which a rattle‐type‐structured carrier enables intraparticle‐double‐scattering to generate massive reactive oxygen species (ROS) during the sonodynamic process. Abundant ROS accumulation can directly kill tumor cells, release antigens, and activate systematic immune responses for expanding effector T or CAR‐T cells, while alleviating ITM via immunosuppressive macrophage polarization and reduction in pro‐tumorigenic cytokine secretion. Furthermore, the co‐loaded phosphodiesterase‐5 inhibitors release nitric oxide (NO) to impel vascular normalization and open the infiltration barrier (IB) for allowing more T cells to enter into the tumor. Systematic experiments demonstrate the feasibility of such intraparticle‐double‐scattering‐decoded sonogenetics in the sonoimmunity‐engineered nanoplatforms for expanding effector T or CAR‐T cells, thereby promoting their infiltration into tumors and alleviating ITM. These compelling actions lead to excellent CAR‐T and ICB immunotherapies against solid tumors with repressed tumor metastasis.