A Robust ROS Generation Strategy for Enhanced Chemodynamic/Photodynamic Therapy via H2O2/O2 Self-Supply and Ca2+ Overloading

The efficacy of cancer therapy with reactive oxygen species (ROS) as the main therapeutic medium suffers from a deficiency of oxy-substrates, for example, insufficient endogenous hydrogen peroxide (H 2 O 2 ) in chemodynamic therapy (CDT) and inherent hypoxia in photodynamic therapy (PDT). Herein, a smart polyethylene glycol (PEG)-ylated nanosystem CaO 2 @ZIF-Fe/Ce6@PEG (abbreviation as CaZFCP) is constructed to achieve H 2 O 2 /O 2 self-supply and Ca 2+ overloading in tumor cells simultaneously for enhanced CDT/PDT. Under the weakly acidic tumor microenvironment, the activity components inside CaZFCP, that is, CaO 2 nanoparticles, Fe 2+ , and photosensitizer Chlorin e6 (Ce6) are released by the degradation of zeolitic imidazole framework-90 (ZIF-90). Thereinto, CaO 2 nanoparticles are further decomposed to generate H 2 O 2 and O 2 , which alleviates both the insufficient endogenous H 2 O 2 and hypoxia in tumor area, thus enhancing the efficiency of CDT and PDT by producing more hydroxyl radicals and singlet oxygen. Furthermore, Ca 2+ overloading induced by the decomposition of CaO 2 is available for amplifying intracellular oxidative stress, resulting in mitochondrial dysfunction, which further improves the efficacy of combined CDT/PDT. In vitro and in vivo experimental results confirm excellent tumor inhibition effect, which also provides a facile paradigm in ROS-involved cancer therapies.