Photoinduced Au-decorated ZnO nanosheets enhance in vitro sonodynamic therapy in breast cancer cells.

Sonodynamic therapy (SDT) is a promising noninvasive cancer treatment, but the performance of semiconductor sonosensitizers is often limited by rapid electron-hole recombination and insufficient reactive oxygen species (ROS) generation. Herein, ZnO-Au nanocomposites were developed by anchoring Au nanoparticles onto ZnO nanosheets through photoinduced deposition, with an actual Au loading of 4.83 wt%. This metal‑semiconductor heterostructure markedly improved charge separation, reduced interfacial charge‑transfer resistance. EPR measurements in cell‑free conditions confirmed enhanced ultrasound‑triggered generation of hydroxyl and superoxide radicals, while ZnO‑Au‑mediated SDT induced increased intracellular total ROS levels in breast cancer cells. Notably, ZnO-Au-mediated SDT produced substantially greater cytotoxicity and clonogenic inhibition than pristine ZnO in both MCF-7 and MDA-MB-231 breast cancer cells. Mechanistically, the enhanced anticancer activity was mainly driven by amplified ROS-mediated oxidative damage, which induced mitochondrial membrane potential collapse and mitochondrial apoptosis, while triggering molecular alterations consistent with ferroptosis via suppression of the SLC7A11/GPX4 antioxidant axis, and suppressing EMT-associated migration and invasion. Transcriptomic analysis further supported this mechanism by revealing activation of oxidative stress and mitochondrial metabolism-related pathways, together with suppression of cell cycle, DNA repair, and nucleocytoplasmic transport programs. Overall, these findings demonstrate that Au decoration enhances the sonodynamic performance of ZnO nanosonosensitizers by promoting charge separation and amplifying ROS-dependent anticancer mechanisms. However, in vivo therapeutic efficacy and biosafety, as well as further functional validation of ferroptosis and p53-dependent apoptotic regulation, remain to be systematically established.