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 H2O2, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) hinder ROS generation significantly. Herein, we reported CaO2@Cu-TCPP/CUR with O-2/H2O2/Ca2+ self-supply and GSH depletion for enhanced PDT/CDT and Ca2+ overload synergistic therapy. CaO2 nanospheres were first prepared and used as templates for guiding the coordination between the carboxyl of tetra-(4-carboxyphenyl)porphine (TCPP) and Cu2+ ions as hollow CaO2@Cu-TCPP, which facilitated GSH-activated TCPP-based PDT and Cu+-mediated CDT. The hollow structure was then loaded with curcumin (CUR) to form CaO2@Cu-TCPP/CUR composites. Cu-TCPP prevented degradation of CaO2, while Cu2+ ions reacted with GSH to deplete GSH, produce Cu+ ions, and release TCPP, CaO2, and CUR. CaO2 reacted with H2O to generate O-2, H2O2, and Ca2+ to achieve O-2/H2O2/Ca2+ self-supply for TCPP-based PDT, Cu+-mediated CDT, and CUR-enhanced Ca2+ overload therapy. Thus, this multilevel ROS amplifier enhances synergistic therapy with fewer side effects and drug resistance.