Leonurus-derived exosome-functionalized hydrogels accelerated diabetic wound healing by regulating...

Diabetic wound (DW) complications, driven by persistent oxidative stress, unresolved inflammation, and vascular dysfunction, present a critical clinical challenge. Although various polypeptide biological dressings continue to be developed, their efficacy is not satisfactory. Plant-to-mammal regulation has provided an effective approach for chronic wound management in recent years, but the development of effective plant-based treatments remains challenging. The use of exosomes (Exos) from Chinese herbs is promising for wound healing. In the present study, Leonurus japonicus Houttuyn (YMC)-originating Exos were isolated and the YMC-Exo engineered hydrogel treatment inhibited stress microenvironment-induced endothelial cell and keratinocyte damage and accelerated DW healing (DWH). Mass spectrometry results for active constituent detection showed that YMC-Exos contained stachydrine (STA). In vitro and in vivo experiments confirmed that the STA treatment reversed stress microenvironment-induced endothelial cell and keratinocyte damage and promoted DWH by promoting Nrf2 expression. Limited proteolysis mass spectrometry detection revealed that KEAP1 was a downstream STA target. KEAP1 overexpression inhibited the nuclear translocation of Nrf2 after the STA treatment, suggesting that STA interacted with KEAP1 and promoted the nuclear translocation of Nrf2. Taken together, the results demonstrated that STA from YMC-Exo engineered hydrogel treatment improved hyperglycemia-induced stress microenvironment by directly binding and inhibiting KEAP1, thereby improving endothelial cell and keratinocyte function and accelerating DWH.