An energy metabolism blockade and redox homeostasis imbalance dual-pathway strategy for H₂S gas-bloomed calcium overload

Hydrogen sulfide (H₂S)-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 H₂S-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 H₂S 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 H₂O₂ while inhibiting COX IV activity and rapidly depleting intracellular adenosine in triphosphate, thus completely blocking the energy supply of tumor cells. This dual-pathway strategy utilizes H₂S gas-bloomed calcium overload to block energy metabolism and induce redox imbalance, providing new insights into exploring energy metabolism blockade as a therapeutic tool for tumor treatment.