A senolysis-targeting bioenergetic nanoplatform for diabetic wound healing

The overaccumulation of senescent cells impedes the healing of diabetic wounds by exacerbating inflammatory responses and metabolic energy expenditure in microenvironment. However, there is currently no effective strategy to target and eliminate the senescent cells. In this work, we have developed a targeted senolytic and bioenergetic hydrogel to precisely harness autophagy-inducing activity for eliminating senescent cells, while simultaneously enhancing energy delivery efficiency to promote wound healing. Briefly, the AICAR-loaded extracellular vesicle with a galactose surface (GEA) exhibits precise targeting of senescence-associated β-galactosidase, and efficiently triggered autophagy-mediated senescent cell death, ultimately alleviating microenvironmental inflammation and oxidative stress. Furthermore, nicotinamide mononucleotide (NMN)-modified hydrogels were utilized for the sustained release of GEAs, and simultaneously enhancing tissue energy supply by NAD+ salvage synthetic pathway. Finally, the composite hydrogel promoted the healing of diabetic wounds via reducing the proportion of senescent cells, suppressing the sustained release of senescence-associated secretory phenotype and reactive oxygen species, and boosting energy production. Therefore, this project develops a multifaceted strategy for diabetic wounds healing featuring both specific-eliminating senescent cells and fostering tissue microenvironment regeneration.