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Although existing radiosensitizers can enhance initial DNA damage, they generally fail to suppress subsequent self\u2010repair of tumor cells and often induce off\u2010target toxicity due to nonspecific activation. Here, we report a hydrated electron ()\u2010activated nano\u2010radiosensitizer (RT\u2010nRS) that enables tumor\u2010confined radiosensitization by converting transient RT\u2010induced damage into persistent subcellular dysfunction. Unlike conventional RT\u2010responsive systems that rely on short\u2010lived reactive oxygen species, RT\u2010nRS leverages the longer lifetime of  to trigger the irradiation\u2010induced zwitterion\u2010to\u2010cationic 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\u2010nRS to induce sustained ER stress, thereby simultaneously amplifying DNA damage and suppressing DNA repair. Our results demonstrate that RT\u2010nRS effectively overcomes tumor radioresistance while minimizing off\u2010target toxicity to non\u2010irradiated normal tissues, leading to significantly enhanced radiotherapy efficacy. Our work establishes hydrated electron\u2010responsive chemistry as a strategy for spatiotemporally controlled radiosensitization and provides a general framework for converting transient radiotherapeutic stimuli into durable biological outcomes.<\/jats:p>","DOI":"10.1002\/anie.6258337","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:54:00Z","timestamp":1792425240000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrated Electron\u2010Activated Nano\u2010Radiosensitizer Induces Sustained Endoplasmic Reticulum Stress for Potent Tumor Radiosensitization"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9643-0517","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine 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