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

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 Au₆Cu₂ (NO₂-Au₆Cu₂) 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 NO₂-Au₆Cu₂ 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.