Tumor Microenvironment-Responsive Cu/CaCO 3 -Based Nanoregulator for Mitochondrial Homeostasis Disruption-Enhanced Chemodynamic/Sonodynamic Therapy.

The efficiency of reactive oxygen species (ROS)-mediated cancer therapy is restrained by intrinsic characteristics in the tumor microenvironment (TME), such as overexpressed glutathione (GSH), hypoxia and limited efficiency of H 2 O 2 . In this work, intelligent copper-dropped calcium carbonate loading sonosensitizer Ce6 nanoparticles (Cu/CaCO 3 @Ce6, CCC NPs) are established to realize TME-responsive self-supply of oxygen and successively Ca 2+ -overloading-strengthened chemodynamic therapy/sonodynamic therapy (CDT/SDT). CCC NPs release Ca 2+ , Cu 2+ , and Ce6 in weakly acid and GSH-excessive TME. Released Cu 2+ can not only consume GSH and turn into Cu + via a redox reaction, but also provide CDT-creating hydroxyl radicals through the Fenton-like reaction. Under ultrasound irradiation, the intracellular oxidative stress is amplified profoundly relying on singlet oxygen outburst from SDT. Moreover, Ca 2+ influx aggravates the mitochondrial disruption, which further accelerates the oxidation level. The facile and feasible design of the Cu-dropped CaCO 3 -based nanoregulators will be further developed as a paradigm in ROS-contributed cancer therapy.