A Radioresistant‐Tumor‐Targeted Nanoparticle for X‐Ray‐Controlled Nitric Oxide Release to Potentiate Radiotherapy

ABSTRACT Nitric oxide (NO) treated radioresistant tumors by relieving hypoxia and blocking DNA repair, but its nonselective toxicity has precluded therapeutic use. Here, we introduce a radioresistant tumor‐selective NO nanogenerator that releases NO exclusively within the irradiated field. We identified BNN6 as a uniquely radiosensitive NO donor and loaded it into Glucose‐Regulated Protein 78 (GRP78)‐targeted nanocarrier to obtain PBTN, exploiting the overexpression of GRP78 in radioresistant cancers for selective accumulation. Upon irradiation, BNN6 undergoes one‐electron reduction to release NO exclusively within the irradiated volume. NO combines radiation‐induced reactive oxygen species to form peroxynitrite, provoking tumor DNA breaks while simultaneously suppressing DNA repair. In CT26 tumor‐bearing mice, the combination of radiotherapy with PBTN and anti‐PDL1 antibody achieved a tumor growth suppression of 96.5% and 80% survival at 40 days post‐treatment. This tumor‐targeted, irradiation‐triggered NO nanogenerator thus offers a safe, precise, and translatable strategy to overcome radioresistance.