Multi-level Reactive Oxygen Species Amplifier to Enhance Photo-/Chemo-Dynamic/Ca 2+ 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.