Ultrasound-augmented enzyodynamic-Ca2+ overload synergetic tumor nanotherapy

The excessive intracellular Ca 2+ can induce oxidative stress, mitochondrial damage and cell apoptosis, which has been extensively explored for tumor therapy. However, the low Ca 2+ accumulation originated from Ca 2+ -based nanosystems substantially weakens the therapeutic effect. Herein, a functional plant polyphenol-appended enzyodynamic nanozyme system CaFe 2 O 4 @BSA-curcumin (abbreviation as CFO-CUR) has been rationally designed and engineered to achieve magnified Ca 2+ accumulation process, deleterious reactive oxygen species (ROS) production, as well as mitochondrial dysfunction through enzyodynamic-Ca 2+ overload synergistic effect. The exogenous Ca 2+ released by CaFe 2 O 4 nanozymes under the weakly acidic tumor microenvironment and Ca 2+ efflux inhibition by curcumin boost mitochondria-dominant antineoplastic efficiency. The presence of Fe components with multivalent characteristic depletes endogenous glutathione and outputs the incremental ROS due to the oxidase-, peroxidase-, glutathione peroxidase-mimicking activities. The ROS burst-triggered regulation of Ca 2+ channels and pumps strengthens the intracellular Ca 2+ accumulation. Especially, the exogenous ultrasound stimulation further amplifies mitochondrial damage. Both in vitro and in vivo experimental results affirm the ultrasound-augmented enzyodynamic-Ca 2+ overload synergetic tumor inhibition outcomes. This study highlights the role of ultrasound coupled with functional nanozyme in the homeostasis imbalance and function disorder of mitochondria for highly efficient tumor treatment.