Abstract

Refractory chronic diabetic wounds severely threaten patient survival; however, current treatments do not adequately promote healing. Cathepsin K (CTSK), a collagen-degrading protease upregulated in early diabetic wounds, presents a potential therapeutic target, and human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUMSC-EVs) show promise in regeneration but are associated with challenges related to production yield and stability. This study hypothesized that combining a stable CTSK inhibitor with hUMSC-EVs could enhance therapeutic efficacy and overcome these challenges. The hypothesis was tested using diabetic wound models in db/db mice with high glucose-exposed human dermal fibroblasts and human umbilical vein endothelial cells. The combination of a CTSK inhibitor and hUMSC-EVs at half doses outperformed full-dose monotherapies, accelerating wound healing through superior effects on collagen synthesis, cell proliferation, migration, and angiogenesis. Mechanistically, the combined treatment promoted wound healing by inhibiting ferroptosis. This strategy demonstrates accelerated wound healing with a lower hUMSC-EV dosage, suggesting promising clinical application potential. ARTICLE HIGHLIGHTS A half-dose combination of a cathepsin K and human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUMSC-EVs) achieved superior diabetic wound healing compared with full-dose monotherapies. The combined therapy more potently suppressed ferroptosis in diabetic wound tissue as well as in high glucose-exposed fibroblasts and endothelial cells. Ferroptosis inhibition enhanced cell survival, migration, angiogenesis, and mitochondrial function in high glucose-exposed fibroblasts and endothelial cells. This dual-target strategy has the potential to reduce the hUMSC-EV dosage while improving wound healing outcomes, thus enhancing clinical potential.