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. 2025 Jul:142:156688.
doi: 10.1016/j.phymed.2025.156688. Epub 2025 Mar 25.

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

Yidan Xia  1 , Beibei Han  1 , Fengyuan Zhang  1 , Qirong Li  2 , Qiang Feng  2 , Shidong Zhang  3 , Da Liu  4 , Chao Lin  5 , Dongxu Wang  6 , Bin Liu  7
Affiliations

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

Yidan Xia et al. Phytomedicine. 2025 Jul.

Abstract

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.

Keywords: Diabetic wound healing; MSC-exo; PF-127; Paeonol; miR-424.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.