DNA‐Capturing Manganese‐Coordinated Chitosan Microparticles Potentiate Radiotherapy via Activating the cGAS‐STING Pathway and Maintaining Tumor‐Infiltrating CD8 + T‐Cell Stemness

Abstract The radiotherapy‐induced release of DNA fragments can stimulate the cyclic guanosine monophosphate‐adenosine monophosphate synthase‐stimulator of interferon genes (cGAS‐STING) pathway to prime antitumor immunity, but this pathway is expected to be less potent because of the inefficient cytosolic delivery of negatively charged DNA fragments. In this study, manganese‐coordinated chitosan (CS‐Mn) microparticles with selective DNA‐capturing capacity are concisely prepared via a coordination‐directed one‐pot synthesis process to potentiate the immunogenicity of radiotherapy. The obtained CS‐Mn microparticles that undergo rapid disassembly under physiological conditions can selectively bind with DNA to form positively charged DNA‐CS assemblies because of the strong electrostatic interaction between linear chitosan and DNA molecules. They thus enable efficient cytosolic delivery of DNA in the presence of serum to cooperate with Mn 2+ to activate the cGAS‐STING pathway in dendritic cells. Upon intratumoral injection, the CS‐Mn microparticles markedly enhance the efficacy of radiotherapy against both irradiated and distal tumors in different tumor models via collectively promoting tumor‐infiltrating CD8 + T‐cell stemness and the activation of innate immunity. The radiosensitization effect of CS‐Mn microparticles can be further augmented by concurrently applying anti‐programmed cell death protein 1 (anti‐PD‐1) immunotherapy. This work highlights an ingenious strategy to prepare Trojan horse‐like DNA‐capturing microparticles as cGAS‐STING‐activating radiosensitizers for effective radioimmunotherapy.