PTEN/PI3K/AKT pathway activation with hypoxia-induced human umbilical vein endothelial cell exosome for angiogenesis-based diabetic skin reconstruction.

Diabetic skin, a major clinical challenge due to impaired wound healing, is often exacerbated by a hypoxic microenvironment at the wound site. Exosomes have been proven to have excellent biological activities and applied to solve many bioengineering problems. However, the wide application of exosomes is still limited by their short in vitro lifetime and low yield. To overcome these application limitations, this study specifically enhances the pro-angiogenic biological efficacy of exosomes through hypoxic treatment and achieves sustained release using hydrogel loading. In vitro, hypoxia-induced exosomes (Hp-Exo) significantly enhanced endothelial cell migration, proliferation, and angiogenic capacity. In vivo, Gelman hydrogels loaded with Hp-Exo accelerated wound closure, promoted collagen deposition, and increased vascularization in diabetic mice. miRNA sequencing of Hp-Exo revealed that exosomes induced under hypoxic conditions contain various miRNAs, which enhance vascular endothelial cell proliferation, migration, and angiogenesis through the PTEN/PI3K/AKT pathway. These results highlight that hypoxia-induced exosomes, when delivered through a biocompatible hydrogel platform, provide potential therapeutic approach to improve diabetic wound healing by stimulating angiogenesis and tissue regeneration.