Cascade-responsive nanobomb with domino effect for anti-tumor synergistic therapies

The development of reactive oxygen species (ROS) generation agents that can selectively produce sufficient ROS at the tumor site without external energy stimulation is of great significance for the further clinical application of ROS-based therapies. Herein, we designed a cascade-responsive ROS nanobomb (ZnO₂@Ce6/CaP@CPPO/BSA, designated as Z@Ce6/CaP@CB) with domino effect and without external stimulation for the specific generation of multiple powerful ROS storms at the tumor site. The calcium phosphate shell and ZnO₂ core gradually degrade and release Ca²⁺, Zn²⁺ and hydrogen peroxide (H₂O₂) under acid stimulation. On the one hand, Zn²⁺ can enhance the generation of endogenous superoxide anions (·O₂ ^-) and H₂O₂ through the inhibition of the mitochondrial electron transport chain. On the other hand, the generation of large amounts of exogenous H₂O₂ can cause oxidative damage to tumor cells and further activate bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate (CPPO)-mediated chemiexcited photodynamic therapy. In addition, the oxidative stress caused by the generated ROS can lead to the uncontrolled accumulation of Ca²⁺ in cells and further result in Ca²⁺ overload-induced cell death. Therefore, the introduction of Z@Ce6/CaP@CB nanobombs triggered the 'domino effect' that caused multiple heavy ROS storms and Ca²⁺ overload in tumors and effectively activated anti-tumor immune response.