Tumor Microenvironment‐Responsive Cu/CaCO₃‐Based Nanoregulator for Mitochondrial Homeostasis Disruption‐Enhanced Chemodynamic/Sonodynamic Therapy

Abstract 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 H₂O₂. In this work, intelligent copper‐dropped calcium carbonate loading sonosensitizer Ce6 nanoparticles (Cu/CaCO₃@Ce6, CCC NPs) are established to realize TME‐responsive self‐supply of oxygen and successively Ca²⁺‐overloading‐strengthened chemodynamic therapy/sonodynamic therapy (CDT/SDT). CCC NPs release Ca²⁺, Cu²⁺, and Ce6 in weakly acid and GSH‐excessive TME. Released Cu²⁺ 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, Ca²⁺ influx aggravates the mitochondrial disruption, which further accelerates the oxidation level. The facile and feasible design of the Cu‐dropped CaCO₃‐based nanoregulators will be further developed as a paradigm in ROS‐contributed cancer therapy.