Effective Amplification of Oxidative Stress and Calcium Manipulation Mediated Mitochondrial Dysfunction Based on Engineered Nanozyme for Primary and Metastatic Breast Cancer Therapy

Abstract Herein, an engineered nanocomposite (FZS HC ) was constructed containing zinc‐based nanozyme(ZS), Hemin and Ca 2+ ions with further surface modification of phospholipid and folic acid (FA) for primary and metastatic breast cancer therapy. During therapy, the FZS HC initially accumulated in tumor tissues through enhanced permeability and retention effectand FA receptor‐mediated tumor‐targeting delivery. After that, the FZS HC further dissociated to free Ca 2+ and Hemin loaded ZS in the acidic environment of lysosome. The resulting ZS then generated reactive oxygen species (ROS) and consumed glutathione via peroxidase and glutathione oxidase mimicking enzyme activities to induce the tumor‐specific ferroptosis for primary tumor elimination, in which the ROS production could be further promoted by the Hemin catalyzed Fenton‐likereactions to amplify oxidative damage and accelerate the ferroptosis. Furthermore, the ROS also influenced calcium metabolism of tumor cells, causingthe Ca 2+ ‐overloading and mitochondrial dysfunction in tumor cell salong with the introduction of exogenous Ca 2+ , which resulted in the suppression of adenosine triphosphate synthesis to hinder the energy supply of tumor cells for significant inhibition of tumor metastasis. Both in vitro and in vivo results demonstrated the remarkable therapeutic slmult1 efficiencyof FZS HC nanozyme in suppressing the growth and metastasis of breastcancer.