A Semiconducting Iron‐Chelating Nano‐immunomodulator for Specific and Sensitized Sono‐metallo‐immunotherapy of Cancer

Abstract Sono‐immunotherapy holds great potential for deep tumor inhibition; however, smart sono‐therapeutic agents to simultaneously eliminate ‘domestic’ tumor cells and regulate the ‘community’ tumor immune microenvironment have rarely been developed. Herein, we report a spatiotemporally controllable semiconducting iron‐chelated nano‐metallomodulator (SINM) for hypersensitive sono‐metallo‐immunotherapy of cancer. SINM consists of a semiconducting polymer (SP) backbone chelating iron ions (Fe 3+ ) with thiophene‐based Schiff base structure, and a hydrophilic side chain. Upon accumulation in tumors after systemic administration, SINM specifically arouses ferroptosis and M1 macrophage polarization due to its response toward the tumor redox environment; meanwhile, the chelation of Fe 3+ enhances the sono‐sensitizing effect of SPs, leading to enhanced generation of reactive oxygen species for immunogenic cell death. Such combined sonodynamic metallo‐immunotherapy of SINM efficiently ablates deep tumor and spatiotemporally regulates immunophenotypes.