Ultrasound-augmented enzyodynamic-Ca²⁺ overload synergetic tumor nanotherapy

The excessive intracellular Ca²⁺ can induce oxidative stress, mitochondrial damage and cell apoptosis, which has been extensively explored for tumor therapy. However, the low Ca²⁺ accumulation originated from Ca²⁺-based nanosystems substantially weakens the therapeutic effect. Herein, a functional plant polyphenol-appended enzyodynamic nanozyme system CaFe₂O₄@BSA-curcumin (abbreviation as CFO-CUR) has been rationally designed and engineered to achieve magnified Ca²⁺ accumulation process, deleterious reactive oxygen species (ROS) production, as well as mitochondrial dysfunction through enzyodynamic-Ca²⁺ overload synergistic effect. The exogenous Ca²⁺ released by CaFe₂O₄ nanozymes under the weakly acidic tumor microenvironment and Ca²⁺ 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 Ca²⁺ channels and pumps strengthens the intracellular Ca²⁺ accumulation. Especially, the exogenous ultrasound stimulation further amplifies mitochondrial damage. Both in vitro and in vivo experimental results affirm the ultrasound-augmented enzyodynamic-Ca²⁺ 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.