Organic AIE Nanoradiosensitizer Potentiates X‐Ray Triggered Continuous Reactive Oxygen Species Generation for Potent Cancer Radioimmunotherapy

Abstract Organic radiosensitizers (ORSs), with structural versatility, hold promise for sensitizing radiotherapy (RT) by interacting with X‐ray photons to generate reactive oxygen species (ROS). They often consist of low‐Z elements that have inherently low X‐ray deposition capability. However, current ORSs suffer from short circulation half‐lives and low tumor retention, contradicting their requirements for sustained ROS generation upon RT in tumor sites. Herein, a glutathione‐responsive system is prepared, loaded with aggregation‐induced emission molecules (TPEPy‐I) and Ferriprotoporphyrin IX chloride (Hemin), to act as an ORS (named THN) for X‐ray triggered sustained ROS generation for efficient antitumor immunotherapy. In detail, THN effectively deposited X‐ray photons, which interact with water molecules to generate abundant ROS under external radiation. Subsequently, THN‐mediated radiosensitization stimulated tumor cells to produce hydrogen peroxide (H ₂ O ₂ ) by upregulating NOX4 protein, promoting the chemodynamic process of Hemin reacting with H ₂ O ₂ to continuously produce hydroxyl radicals. The double‐promoting ROS generation of THN induced massive immunogenic cancer cell death and polarized M2 macrophages into the M1 phenotype for enhanced antitumor immunotherapy. Experiments revealed that THN‐sensitized RT inhibited tumor recurrence and increased memory T‐cell proportion for long‐term antitumor immunity. The developed ORS has great clinical potential as both a radiosensitizer and a post‐RT immunomodulatory agent.