PtMo‐Au Metalloenzymes Regulated Tumor Microenvironment for Enhanced Sonodynamic/Chemodynamic/Starvation Synergistic Therapy

Abstract The clinical application of sonodynamic therapy (SDT) is greatly limited by the low quantum yield of sonosensitizers and tumor microenvironment (TME). Herein, PtMo‐Au metalloenzyme sonosensitizer is synthesized by modulating energy band structure of PtMo with Au nanoparticles. The surface deposition of Au simultaneously solves the carrier recombination and facilitates the separation of electrons (e − ) and holes (h + ), effectively improving the reactive oxygen species (ROS) quantum yield under ultrasound (US). The catalase‐like activity of PtMo‐Au metalloenzymes alleviates hypoxia TME, thus enhancing the SDT‐induced ROS generation. More importantly, tumor overexpressed glutathione (GSH) can serve as the hole scavenger, which is accompanied by a persistent depletion of the GSH, thus inactivating GPX4 for the accumulation of lipid peroxides. The distinctly facilitated SDT‐induced ROS production is coupled with chemodynamic therapy (CDT)‐induced hydroxyl radicals (•OH) to exacerbate ferroptosis. Furthermore, Au with glucose oxidase mimic activity can not only inhibit intracellular adenosine triphosphate (ATP) production and induce tumor cell starvation but also generate H 2 O 2 to facilitate CDT. In general, this PtMo‐Au metalloenzyme sonosensitizer optimizes the defects of conventional sonosensitizers through surface deposition of Au to regulate TME, providing a novel perspective for US‐based tumor multimodal therapy.