AVisible-Light Photocatalysis/HydrolysisHydrogen-GeneratingNanoplatform for Dynamic Inflammation Management via Immune MetabolismOrchestration during Wound Repair

Effective management of inflammation is one of the promising strategies to prevent the formation of chronic wounds. Despite hydrogen being a prospective molecule for anti-inflammatory effects, the on-demand delivery of hydrogen that could synchronize with the dynamic inflammation stages has yet remained unaddressed. Moreover, its specific immunomodulatory mechanisms are still veiled. In this study, we introduced ISO-ZIF-8@AB, a hydrogen-generating nanoplatform that integrated visible-light photocatalysis and hydrolysis reactions to achieve controllable hydrogen release on demand, functioning with an initial peak release and following a sustained release. With ISO-ZIF-8@AB further loaded into an aligned ECM-like scaffold, the complex significantly alleviated inflammation and prevented protracted unhealing. The bulk-RNA sequencing combined with single-cell RNA sequencing revealed that hydrogen treatment effectively reduced the excessive aggregation and infiltration of innate immune cells. Specifically, hydrogen reduced the proportion of <i>Ptgs2+Nos2+</i> pro-inflammatory macrophages (PIMs) by mitigating mitochondrial stress and suppressing HIF-1α-induced glycolysis, the immune-metabolic regulation of which reduced harmful crosstalk between PIMs and hypodermal fibroblasts and facilitated extracellular matrix production accompanied by the ultimate wound repair. Overall, this study presented a strategy for controllable hydrogen release in terms of timing and rate, with further discussions regarding the underlying immune-metabolic regulation mechanisms of hydrogen therapy.