Synchronous Interventions of Glucose and Mitochondrial Metabolisms for Antitumor Bioenergetic Therapy

Abstract Hydrogen sulfide (H₂S)‐based mitochondrial bioenergetic intervention is an attractive therapeutic modality. However, its therapeutic efficacy is limited owing to metabolic plasticity, which allows tumors to shift their metabolic phenotype between oxidative phosphorylation and glycolysis for energy compensation. To overcome this flexibility, a glycopolymer containing a caged H₂S and hydrogen peroxide (H₂O₂) dual‐donor (1‐thio‐β‐D‐glucose [thioglucose]) is synthesized to wrap glucose oxidase (GOx) for complete depletion of tumorigenic energy sources. The loaded GOx catalyzes the glutathione‐activated thioglucose to generate cytotoxic H₂S/H₂O₂, which further induces synergistic defects in mitochondrial function by suppressing cytochrome c oxidase expression and damaging the mitochondrial membrane potential. GOx also blocks glycolysis by depleting endogenous glucose. This synchronous intervention strategy exhibits good anticancer performance, broadening the horizon of antitumor bioenergetic therapy.