TME-responded Full-biodegradable nanocatalyst for mitochondrial calcium Overload-induced hydroxyl radical bursting cancer treatment

Mitochondrial calcium ions (Ca2+) overload, an abnormal accumulation of free Ca2+ in mitochondrial, has become a potential strategy for effective cancer treatment. Inspired by mitochondrial Ca2+ overload-induced ROS generation, a tumor microenvironment (TME)-responded full-degradable ACC@Cu2O-TPP NCs are successfully fabricated for effective chemodynamic therapy (CDT) via toxic hydroxyl radical (∙OH) bursting. The as-synthesized nanocatalysts are stable and safe in normal tissues but will quickly degrade into Ca2+ and cuprous ions (Cu+) under the acidic TME. The mitochondrial Ca2+ overload effectively simulates extra H2O2 generation. Then Cu+ catalyzes the produced H2O2 into toxic ∙OH to kill the tumor cells via Fenton-like reaction. Meanwhile, abundant GSH in tumor cells can further reduce Cu2+ into Cu+ to enhance the CDT effect. Both in vitro and in vivo evaluations demonstrate the efficient anti-tumor effect of ACC@Cu2O-TPP NCs via mitochondrial Ca2+ overload-induced ∙OH bursting. We believe that the development of ACC@Cu2O-TPP NCs will be an amazing inspiration for designing safe and green chemodynamic nanocatalysts for highly efficient cancer treatment.