Au–ZnO Nanomatches as Radiosensitizers with Improved Reactive Oxygen Species Generation and Tumor Hypoxia Modulation for Enhanced Radiotherapy on Triple-Negative Breast Cancer

Despite that radiotherapy (RT) is a prevalent treatment of cancer, enhancing tumor dose deposit and reversing resistance are two major challenges in its clinical application. Here, we report Au–ZnO (AZ) nano matches that drastically increase reactive oxygen species (ROS) generation and alleviate hypoxia in RT on triple-negative breast cancer. Upon X-ray irradiation, Au increases X-ray attenuation and excites the adjacent ZnO by electron scattering, electron transfer, and energy transfer. Meanwhile, Au plays the role of a reservoir of electrons that promotes the charge separation in ZnO, thereby significantly improving the ROS production efficiency and causing the ROS burst. The ROS generation efficiency of AZ is determined to be 2.03 times that of Au. In contrast, a physical mixture of Au and ZnO only slightly increased the ROS generation compared to Au (1.18 times). Moreover, AZ catalyzes H₂O₂ decomposition to produce oxygen at excited states, thus modulating tumor hypoxia. Clonogenic assay showed that AZ had efficient radiosensitization with radiation enhancement factors of 4.01 and 3.50 in 4T1 breast cancer cells under normoxia and hypoxia, respectively. AZ-enhanced RT can successfully eliminate or shrink tumors (two of the six were completely removed) upon 4 Gy of X-ray irradiation on 4T1 tumor-bearing mice. At the end point, the average tumor size in AZ with the RT-treated group was only 1.8% of that of PBS with RT, significantly outperforming the other control groups including a physical mixture of Au and ZnO nanoparticles at the same concentrations..