Hijacking Tumor GLUT1 With a Disassemblable Self‐Enhancing Nanoreactor for Metabolic Exhaustion and Anti‐Angiogenesis

While tumor cells exhibit a well‐known dependence on glucose, effectively exploiting this vulnerability has been challenging. Achieving sustained and intensive glucose consumption and overcoming tumor metabolic adaptability as well as compensatory angiogenesis remain unsolved problems. This study developed a disassemblable, self‐enhancing nanoreactor (GCG). The design centers on a positive feedback loop built upon the glucose transporter GLUT1. GCG is efficiently internalized by hijacking GLUT1, which is overexpressed on tumor cells. Once inside the tumor‐specific high‐glutathione (GSH) environment, it disassembles and activates glucose oxidase (GOx), leading to rapid intracellular glucose depletion. This deprived state, in turn, induces up‐regulation of GLUT1 expression in tumor cells, recruiting more GCG nanoreactors and establishing a self‐enhancing cycle of glucose deprivation. These results indicated that this strategy enabled rapid and sustained glucose consumption in the oxygen‐rich superficial regions of tumors, thereby cutting off the nutrient supply to deeper tumor areas and successfully inducing disulfidptosis via NADPH exhaustion. Concurrently, the resulting extreme glucose scarcity effectively inhibited endothelial cell sprouting and migration, achieving synergistic anti‐angiogenesis. Consequently, this self‐enhancing metabolic intervention exhibited superior tumor suppression (87% inhibition) and anti‐metastatic efficacy. Importantly, it presents a promising therapeutic strategy for tumor therapy by orchestrating self‐enhancing glucose deprivation.