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 Mn²⁺ 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.