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 O₂/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 O₂, H₂O₂, and Ca²⁺ to achieve O₂/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.