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

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 (H₂O₂) by upregulating NOX4 protein, promoting the chemodynamic process of Hemin reacting with H₂O₂ 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.