Pae/exo@PF-127 promote diabetic wound healing through miR-424–5p

BACKGROUND: Currently, chronic diabetic wound healing is one of the urgent clinical challenges. Choosing appropriate dressings loaded with stem cell-derived exosomes (exo) and traditional Chinese medicine extracts that promote healing is an effective method to accelerate skin healing in diabetes. Paeonol (Pae), possessing anti-inflammatory properties and vascular enhancement functions, can serve as a therapeutic herbal extract for treating diabetic wounds. METHODS: Exo were extracted from mesenchymal stem cells and loaded them with Pae (Pae/exo). The effects of Pae/exo on human skin fibroblasts (HSF) and human umbilical vein endothelial cells (HUVEC) were evaluated using CCK-8, migration, and transwell assays. Western blotting, qPCR, and immunofluorescence experiments were conducted to analysis the regulation of associated genes and proteins. Mimics and inhibitors of miR-424-5p were synthesized to further investigate its role in HUVEC and HSF. Additionally, diabetic mice models were constructed with the knockout of miR-322 (a homologous miRNA of miR-424) to validate the impact of miR-424-5p knockout on diabetic skin healing in vivo. To better simulate clinical application, thermosensitive hydrogel Pluronic® F-127 (PF-127) was used as a carrier for Pae/exo, and the effect of Pae/exo@PF-127 on wound healing in diabetic mice was investigated. RESULTS: This study confirmed that Pae/exo increased the proliferation and migration of HSF and HUVEC by promoting epithelial-mesenchymal transition (EMT) and angiogenesis. The expression of miR-424-5p was significantly upregulated upon treatment with Pae/exo, which correlated with the induction of EMT and angiogenesis. In vivo experiments demonstrated that the wound healing rate was significantly lower in miR-322-knockout diabetic mice compared to wild-type diabetic mice; vascular production and epithelialization rate were also reduced in the knockout mice. Pae/exo@PF-127 significantly improved wound healing efficiency in diabetic mice by enhancing EMT and promoting blood vessel formation. The integration of pae, MSC-exo, and PF-127 harnesses their synergistic effects to significantly enhance wound healing and prolong the interval between dressing changes, thereby alleviating patient discomfort. CONCLUSION: Pae/exo@PF-127 promotes EMT and angiogenesis by upregulating miR-424-5p expression, thereby facilitating diabetic wound healing.