Hydrated Electron‐Activated Nano‐Radiosensitizer Induces Sustained Endoplasmic Reticulum Stress for Potent Tumor Radiosensitization

ABSTRACT Radiotherapy (RT) efficacy is often limited by two key challenges: rapid restoration of tumor genomic integrity through DNA repair and the lack of tumor‐confined radiosensitization. Although existing radiosensitizers can enhance initial DNA damage, they generally fail to suppress subsequent self‐repair of tumor cells and often induce off‐target toxicity due to nonspecific activation. Here, we report a hydrated electron ()‐activated nano‐radiosensitizer (RT‐nRS) that enables tumor‐confined radiosensitization by converting transient RT‐induced damage into persistent subcellular dysfunction. Unlike conventional RT‐responsive systems that rely on short‐lived reactive oxygen species, RT‐nRS leverages the longer lifetime of to trigger the irradiation‐induced zwitterion‐to‐cationic surface transformation, thereby maintaining systemic circulation stability while enhancing tumor cellular internalization. Furthermore, preferential accumulation and prolonged retention within the endoplasmic reticulum (ER) enable RT‐nRS to induce sustained ER stress, thereby simultaneously amplifying DNA damage and suppressing DNA repair. Our results demonstrate that RT‐nRS effectively overcomes tumor radioresistance while minimizing off‐target toxicity to non‐irradiated normal tissues, leading to significantly enhanced radiotherapy efficacy. Our work establishes hydrated electron‐responsive chemistry as a strategy for spatiotemporally controlled radiosensitization and provides a general framework for converting transient radiotherapeutic stimuli into durable biological outcomes.