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

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 H₂O₂ supply and over-expression of glutathione (GSH) in the tumor microenvironment (TME). Herein, a biodegradable self-supplying H₂O₂ nano-enzyme of CuO₂@CaP with a GSH-consumption effect is designed for cascade enhanced CDT to overcome the problem of H₂O₂ deficiency and GSH overexpression. In this design, CuO₂@CaP is gradually degraded to Ca²⁺, Cu²⁺, and H₂O₂ in acidic TME, resulting in synergistically enhanced CDT owing to the efficient self-supplied H₂O₂ and GSH-depletion and Ca²⁺ overload therapy. Interestingly, the faster degradation of CuO₂@CaP and promoted production rate of •OH are further achieved after triggering with ultrasound (US). And, the US-enhanced CDT and Ca²⁺ overload synergistic antitumor therapy is successfully achieved in vivo. These findings provide a promising strategy for designing biodegradable nano-enzymes with self-supplying H₂O₂ and GSH consumption for US-mediated CDT.