Enhanced Sonodynamic Cancer Therapy through Boosting Reactive Oxygen Species and Depleting Glutathione

The complex tumor microenvironment (TME) affects reactive oxygen species (ROS)-based therapies; breaking the limitations of the TME to enhance the effectiveness of sonodynamic therapy (SDT) is full of great challenges. Herein, iron atomically dispersed nanoparticles (Fe-N-C) were first reported as sonosensitizers with highly efficient ROS generation by overcoming TME limitations. Its peroxidase and catalase-like activities catalyze H2O2 to produce highly toxic <middle dot>OH and in situ O2, respectively, and then O2 molecules adsorbed at Fe active sites obviously lower the energy barrier for <middle dot>OH formation. Meanwhile, its glutathione-oxidase-like activity can rapidly consume glutathione (GSH) in the TME to induce tumor cell apoptosis and ferroptosis. Density functional theory calculation results elucidate the possible mechanism of ROS generation: O2 molecules are activated by receiving sonoelectrons to generate <middle dot>O2 -, which further reacts with H2O to produce OH-. Then OH- is oxidized by sonoholes to form <middle dot>OH. Fe-N-C displays a superior tumor specificity SDT.