Au ₆ Cu ₂ Clusters with High Electron Affinity and Oxygen‐Mimetic Properties for Hypoxic Tumor Radiosensitization

Abstract Hypoxia‐induced radioresistance primarily contributes to the failure of radiotherapy because it hinders the effective fixation of DNA damage. Despite the considerable antitumor activity of chemical molecules such as electron‐affinic nitroimidazoles affirmed by clinical studies, their dose‐dependent side effects and low radiotherapy efficacy have become major drawbacks. In this study, we synthesized nitrobenzene‐functionalized Au 6 Cu 2 (NO 2 ‐Au 6 Cu 2 ) clusters, integrating metal clusters with chemical radiosensitizers. The ligand 4‐nitrophenylacetylene's hypoxia‐selective toxicity arises from reductase‐mediated radical generation under hypoxia, depleting GSH and compromising radiotherapy ROS clearance. Our findings indicate that the electron affinity of interfacial ligands has a significant effect on the electron affinity and hypoxic cytotoxicity of metal clusters. Experimental results demonstrated that NO 2 ‐Au 6 Cu 2 clusters exhibit a high sensitization enhancement ratio by leveraging the properties of gold clusters to augment radiotherapy and the oxygen‐mimetic property of chemical molecules to impair DNA repair pathways. This research introduces a novel strategy for developing highly efficient metal cluster‐based hypoxic radiosensitizers.