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

Herein, an engineered nanocomposite (FZS_HC) was constructed containing zinc-based nanozyme(ZS), Hemin and Ca²⁺ 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 Ca²⁺ 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 Ca²⁺-overloading and mitochondrial dysfunction in tumor cell salong with the introduction of exogenous Ca²⁺, 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.