Transformable albumin-based nanocapsules selectively amplify tumor starvation and disulfidptosis through metabolic deception

Starvation-based therapy has emerged as a promising approach for cancer treatment. However, tumors can effectively circumvent nutrient deprivation by enhancing the uptake of alternative nutrients such as albumin to attenuate the efficacy of starvation-inducing drugs. In this study, we aimed to exploit the compensatory ability of tumors for alternative nutrients to improve the selectivity of starvation therapy. Albumin nanocapsules were coupled with glucose oxidase (GOX) and loaded with V9302 to obtain nutrient-mimicking transformable nanocapsules (HGV) that induced glucose and glutamine depletion. The HGV entered tumors efficiently owing to their transformability and induced starvation, which in turn upregulated the albumin uptake of the tumors to further increase the internalization of nanocapsules as a positive feedback loop. This amplified starvation led to a significant accumulation of intracellular disulfides and triggered disulfidptosis in the tumor cells, which not only effectively inhibited the growth of primary tumors but also stimulated antitumor immune responses. Furthermore, the tumor selectivity of HGV reduced the hepatotoxicity of GOX and V9302, making it a potential translational starvation-inducing nanocapsule.