Hydrogen sulfide-driven Janus nanoplatforms for comprehensive disruption of intracellular glucose metabolism and activation of disulfidptosis.

Glucose metabolism (GM) supplies energy and maintains redox homeostasis to support tumor proliferation, while the compensatory crosstalk among multiple GM pathways enables tumor cells to adapt to metabolic perturbations and sustain growth. Therefore, comprehensively blocking GM may dismantle this compensatory network and improve antitumour efficacy. Here, Janus-structured dendritic silica containing disulfide bonds and ZIF-90 loaded with quercetin (Qu) were synthesized to form DZQPP nanoparticles for systematic GM disruption. After reaching the tumor site, cleavage of the tetrasulfide bridges in dendritic mesoporous silica (DMON) releases hydrogen sulfide (H₂S), ZIF-90 degrades to liberate Zn2+, and quercetin is simultaneously released. H₂S suppresses oxidative phosphorylation by inhibiting cytochrome c oxidase IV (COX IV), whereas Zn2+ and Qu inhibit glycolysis and the pentose phosphate pathway, respectively. As a result, GM and its compensatory network are comprehensively disrupted, leading to redox imbalance and marked depletion of intracellular adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH). In addition, H₂S generation at one end of the Janus structure provides self-propulsion capability, enhancing cellular uptake and therapeutic efficacy. Overall, DZQPP effectively disrupts GM, thereby dismantling its compensatory network, inducing oxidative stress and intracellular disulfide accumulation, which subsequently triggers disulfidptosis and suppresses liver tumor growth.