Hydrated Electron-Activated Nano-Radiosensitizer Induces Sustained Endoplasmic Reticulum Stress for Potent Tumor...

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 ( $e_{\mathrm{aq}}^{-}$ )-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 $e_{\mathrm{aq}}^{-}$ 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.