Tumor Microenvironment Cascade Activated Biodegradable Nano‐Enzymes for Glutathione‐Depletion and Ultrasound‐Enhanced Chemodynamic Therapy

Abstract Chemodynamic therapy (CDT) is emerged as a novel and promising tumor therapy by using the powerful reactive oxygen species (ROS) to kill cancer cells. However, the current CDT is remarkably inhibited due to insufficient H 2 O 2 supply and over‐expression of glutathione (GSH) in the tumor microenvironment (TME). Herein, a biodegradable self‐supplying H 2 O 2 nano‐enzyme of CuO 2 @CaP with a GSH‐consumption effect is designed for cascade enhanced CDT to overcome the problem of H 2 O 2 deficiency and GSH overexpression. In this design, CuO 2 @CaP is gradually degraded to Ca 2+ , Cu 2+ , and H 2 O 2 in acidic TME, resulting in synergistically enhanced CDT owing to the efficient self‐supplied H 2 O 2 and GSH‐depletion and Ca 2+ overload therapy. Interestingly, the faster degradation of CuO 2 @CaP and promoted production rate of •OH are further achieved after triggering with ultrasound (US). And, the US‐enhanced CDT and Ca 2+ overload synergistic antitumor therapy is successfully achieved in vivo. These findings provide a promising strategy for designing biodegradable nano‐enzymes with self‐supplying H 2 O 2 and GSH consumption for US‐mediated CDT.