Enhanced SonodynamicCancer Therapy through BoostingReactive 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.