Multi-level Reactive Oxygen Species Amplifier to Enhance Photo-/Chemo-Dynamic/Ca²⁺ Overload Synergistic Therapy

Reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) hold great promise for tumor treatment. However, hypoxia, insufficient H 2 O 2, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) hinder ROS generation significantly. Herein, we reported CaO 2 @Cu-TCPP/CUR with O 2 /H 2 O 2 /Ca 2+ self-supply and GSH depletion for enhanced PDT/CDT and Ca 2+ overload synergistic therapy. CaO 2 nanospheres were first prepared and used as templates for guiding the coordination between the carboxyl of tetra-(4-carboxyphenyl)porphine (TCPP) and Cu 2+ ions as hollow CaO 2 @Cu-TCPP, which facilitated GSH-activated TCPP-based PDT and Cu + -mediated CDT. The hollow structure was then loaded with curcumin (CUR) to form CaO 2 @Cu-TCPP/CUR composites. Cu-TCPP prevented degradation of CaO 2, while Cu 2+ ions reacted with GSH to deplete GSH, produce Cu + ions, and release TCPP, CaO 2, and CUR. CaO 2 reacted with H 2 O to generate O 2, H 2 O 2, and Ca 2+ to achieve O 2 /H 2 O 2 /Ca 2+ self-supply for TCPP-based PDT, Cu + -mediated CDT, and CUR-enhanced Ca 2+ overload therapy. Thus, this multilevel ROS amplifier enhances synergistic therapy with fewer side effects and drug resistance.