Cascade nanozymes based on glucose oxidase modified gold nanoclusters for enhanced synergistic cancer therapy via activated autophagy and apoptosis.

Although cascade strategy based on starvation therapy and nanozymes synergistic therapy has shown its unique advantages in tumor treatment, the relatively large size of integrated nanoplatform and protective autophagy greatly reduces the therapeutic effects. Herein, we report an ultra-small cascade nanozyme for enhanced synergistic cancer therapy by using glucose oxidase (GOx) capped gold nanoclusters (AuNCs@GOx). The constructed AuNCs@GOx integrates starvation therapy, chemo-dynamic therapy (CDT) and autophagy modulation, which realizes efficient tumor treatment. GOx converts glucose into gluconic acid and HO, followed by the transformation from HO to high-toxic ·OH via peroxidase mimic AuNCs. Notably, AuNCs@GOx activate autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway and activating AMPK/mTOR/ULK1 signaling pathway in Hela cells, thereby synergizing with mitochondrial apoptosis to induce tumor cell death. In vitro experiments using multiple cancer cell lines (SKOV-3, MCF-7, HT-29, Hela and 4 T1) and normal cells (GES-1 and 293 T) demonstrates that AuNCs@GOx could specifically and significantly suppress the cancer cells growth without damaging the normal cells. Furthermore, AuNCs@GOx could effectively inhibit 4 T1 tumor growth with good biocompatibility in vivo. Overall, the introduction of AuNCs@GOx into tumor cells realizes effective cascade treatment of tumor, which induces enhanced CDT and starvation therapy through activating autophagy-mediated death pathway and inducing apoptosis.