Cancer starvation therapy, an effective cancer treatment approach that targets altered metabolic requirements of cancer cells, holds great promise for various cancer treatments. Herein, based on metabolic heterogeneity and hypoxia characteristics of the tumor, Au@BSA-L nanoparticles (NPs) were synthesized via the crosslink of Au@BSA by a hypoxia-responsive linker and utilized as the carrier for wzb117 to obtain Au@BSA-L-wzb117 NPs for hypoxia-activated starvation therapy with enhanced efficiency and negligible side effects. Specifically, the glucose oxidase (GOx)-like catalytic activity of Au@BSA could be effectively shielded during blood circulation owing to the crosslink, endowing Au@BSA-L-wzb117 with good biosafety. When Au@BSA-L-wzb117 accumulated at tumor sites, the hypoxic tumor microenvironment (TME) would promote the cleavage of the linker, resulting in the rapid release of Au@BSA and wzb117. The recovered GOx-mimicking activity of Au@BSA could speed up glucose consumption. Meanwhile, wzb117, a Glucose Transporter 1 (GLUT1) inhibitor, can effectively decrease glucose uptake and induce energy crisis in cancer cells to induce cell apoptosis. Both in vitro and in vivo experiments evidenced that the as-prepared Au@BSA-L-wzb117 exhibited TME hypoxia-responsive reactivity, nutrient consumption, and nutrient supply inhibition of tumor cells, and realized effective inhibition of tumor growth. Through this two-pronged strategy, Au@BSA-L-wzb117 exhibited great promise in efficient tumor starvation therapy with high specificity and reduced side effects.

Hypoxia-responsive nanoparticles for tumor-specific starvation therapy via a two-pronged approach