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.

中文翻译：

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同步干预葡萄糖和线粒体代谢用于抗肿瘤生物能量治疗

基于硫化氢（H ₂ S）的线粒体生物能干预是一种有吸引力的治疗方式。然而，由于代谢可塑性，其治疗功效受到限制，代谢可塑性允许肿瘤在氧化磷酸化和糖酵解之间转变其代谢表型以进行能量补偿。为了克服这种灵活性，合成了一种含有笼状 H ₂ S 和过氧化氢 (H ₂ O ₂ ) 双供体（1-硫代-β -D-葡萄糖 [硫代葡萄糖]）的糖聚合物来包裹葡萄糖氧化酶 (GOx)，以完成致瘤能源的耗尽。负载的GOx催化谷胱甘肽激活的硫代葡萄糖产生细胞毒性的H ₂ S/H ₂ O ₂，​​通过抑制细胞色素c氧化酶的表达和破坏线粒体膜电位进一步诱导线粒体功能的协同缺陷。GOx 还通过消耗内源性葡萄糖来阻止糖酵解。这种同步干预策略表现出良好的抗癌性能，拓宽了抗肿瘤生物能治疗的视野。