Ultrasound-augmented enzyodynamic-Ca2+ overload synergetic tumor nanotherapy

Abstract

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.

Keywords: Ca(2+) overload; Curcumin; Mitochondrial dysfunction; Multienzyme-mimicking; Ultrasound.