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 ·OH and <i>in situ</i> O₂, respectively, and then O₂ molecules adsorbed at Fe active sites obviously lower the energy barrier for ·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 ·O₂^-, which further reacts with H₂O to produce OH^-. Then OH^- is oxidized by sonoholes to form ·OH. Fe-N-C displays a superior tumor specificity SDT.