An energy metabolism blockade and redox homeostasis imbalance dual-pathway strategy for H 2 S gas-bloomed calcium overload

作者：Shiyu Zhang, Xiaoling Zhang, Jianye Wei, E Jiaoting, Siyi Li, Jiaming Wu, Fei He, Shili Gai, Elyor Berdimurodov, Avez Sharipov, He Ding, Piaoping Yang · 发表于：Nano Research · 年份：2024 · DOI：10.26599/nr.2025.94907596 · 被引用次数：2 · 研究领域：Sulfur Compounds in Biology、Enzyme function and inhibition、Redox biology and oxidative stress

Hydrogen sulfide (H 2 S)-based mitochondrial energy metabolism blockade is an attractive tumor therapeutic modality. However, it is limited owing to metabolic plasticity, which allows tumors to shift their metabolic phenotype between oxidative phosphorylation and glycolysis for energy compensation. Herein, a hollow-hierarchical H 2 S-multistage blasting nanomedicine was designed for a dual-pathway strategy targeting the blockade of energy metabolism and the imbalance of redox homeostasis. The tetrasulfide bond-modified hollow-hierarchical structure presents in-situ H 2 S long-term bursting under the intracellular overexpressed glutathione (GSH), which inhibits the expression of the electron transport chain complex cytochrome C (COX IV) for restraining mitochondrial bioenergy supply and causes the energy metabolism blockade. Meanwhile, the Prussian blue in the home position, with thermal-enhanced peroxidase enzymatic activity, could simultaneously generate highly toxic hydroxyl radicals and exacerbate the GSH depletion process, thus further disrupting intracellular redox homeostasis. Mainly, externally encapsulated calcium can induce intracellular acidification and calcium overload, which aggravates mitochondrial dysfunction. The loaded glucose oxidase competes for intracellular glycolytic substrates, generating endogenous H 2 O 2 while inhibiting COX IV activity and rapidly depleting intracellular adenosine in triphosphate, thus completely blocking the energy supply of tumor...