Cascade Nanozymes Based on 'Butterfly Effect' for Enhanced Starvation Therapy via Autophagy Regulation Strategy

Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency still might be weakened by autophagy, a self-protection mechanism under starved stress in tumor. Interestingly, overactivated autophagy can not only improve starvation therapy efficacy but also induce autophagic death. Herein, we report a cascade nanozyme for enhanced starvation therapy by inducing overactivated autophagy. Firstly, glucose oxidase (GOx) modified metal-organic frameworks (NH2-MIL88, MOF) are constructed (MOF-GOx). After loading with curcumin (Cur), the Cur@MOF-GOx are furthermore decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozyme. GOx can catalyze glucose into H2O2 and gluconic acid, which not only leads to tumor starvation, but also provides reactants for Fenton reaction mediated by MOF to generate hydroxyl radicals (•OH) for chemodynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be overactivated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemodynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a “butterfly effect”, which induces enhanced starvation therapy through subsequent autophagic cell death to completely breaks the self-protective mechanism of cancer cells, and generates •OH for chemodynamic therapy . By precise design, the cascade nanozyme realize efficient cancer treatment to restrain regression and metastasis.