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Here, we introduce a radioresistant tumor\u2010selective NO nanogenerator that releases NO exclusively within the irradiated field. We identified BNN6 as a uniquely radiosensitive NO donor and loaded it into Glucose\u2010Regulated Protein 78 (GRP78)\u2010targeted nanocarrier to obtain PBTN, exploiting the overexpression of GRP78 in radioresistant cancers for selective accumulation. Upon irradiation, BNN6 undergoes one\u2010electron reduction to release NO exclusively within the irradiated volume. NO combines radiation\u2010induced reactive oxygen species to form peroxynitrite, provoking tumor DNA breaks while simultaneously suppressing DNA repair. In CT26 tumor\u2010bearing mice, the combination of radiotherapy with PBTN and anti\u2010PDL1 antibody achieved a tumor growth suppression of 96.5% and 80% survival at 40 days post\u2010treatment. This tumor\u2010targeted, irradiation\u2010triggered NO nanogenerator thus offers a safe, precise, and translatable strategy to overcome radioresistance.<\/jats:p>","DOI":"10.1002\/advs.202518233","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T14:58:19Z","timestamp":1776869899000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Radioresistant\u2010Tumor\u2010Targeted Nanoparticle for X\u2010Ray\u2010Controlled Nitric Oxide Release to Potentiate Radiotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Wanze","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology China\u2010Japan Union Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology National Cancer 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