Integrated cascade catalysis of AuPtCu nanozymes and glycolysis inhibition for synergistic breast cancer therapy via metabolism regulation

Nanozymes have emerged as powerful therapeutic agents due to their robust catalytic performance, but their efficacy is often constrained by the complex tumor microenvironment (TME) and the unique metabolic pathway of cancer cells. To overcome this circumstance, a multifunctional nanoplatform (G5.NHAc-PG@APC) was developed to integrate targeted triple-enzyme cascade catalysis with responsive glycolytic inhibition. By using phenylboronic acid (PBA)-modified G5 PAMAM dendrimers as targeted nanocarriers, trimetallic AuPtCu nanozymes were encapsulated, followed by conjugating the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) via pH-responsive boronate ester linkages. The resulting G5.NHAc-PG@APC nanoplatform could target sialic acid-overexpressing tumor cells and exhibit triple SOD/CAT/POD-like enzymatic activities for cascade catalytic therapy to effectively convert endogenous superoxide anions and hydrogen peroxide into lethal hydroxyl radicals (˙OH) while simultaneously generating oxygen to alleviate tumor hypoxia. Furthermore, the co-delivered 2-DG could be responsively released at the TME to inhibit aerobic glycolysis, thereby depriving the intracellular adenosine triphosphate (ATP) and reducing the generation of glutathione (GSH). In vivo studies in a 4T1 tumor-bearing mouse model confirmed that this synergistic strategy of metabolic starvation and sustained oxidative stress could effectively inhibit tumor growth and suppress pulmonary metastasis, while alleviating hypoxia. This work provides a versatile framework for the design of multimetallic nanozymes and multi-pathway synergistic strategies for advanced cancer therapy.