There is a need to find better strategies to promote wound healing, especially of chronic wounds, which remain a challenge. We found that synovium mesenchymal stem cells (SMSCs) have the ability to strongly promote cell proliferation of fibroblasts; however, they are ineffective at promoting angiogenesis. Using gene overexpression technology, we overexpressed microRNA‐126‐3p (miR‐126‐3p) and transferred the angiogenic ability of endothelial progenitor cells to SMSCs, promoting angiogenesis. We tested a therapeutic strategy involving controlled‐release exosomes derived from miR‐126‐3p‐overexpressing SMSCs combined with chitosan. Our in vitro results showed that exosomes derived from miR‐126‐3p‐overexpressing SMSCs (SMSC‐126‐Exos) stimulated the proliferation of human dermal fibroblasts and human dermal microvascular endothelial cells (HMEC‐1) in a dose‐dependent manner. Furthermore, SMSC‐126‐Exos also promoted migration and tube formation of HMEC‐1. Testing this system in a diabetic rat model, we found that this approach resulted in accelerated re‐epithelialization, activated angiogenesis, and promotion of collagen maturity in vivo. These data provide the first evidence of the potential of SMSC‐126‐Exos in treating cutaneous wounds and indicate that modifying the cells—for example, by gene overexpression—and using the exosomes derived from these modified cells provides a potential drug delivery system and could have infinite possibilities for future therapy. Stem Cells Translational Medicine 2017;6:736–747

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Chronic wounds are one of the most serious complications of diabetes mellitus. Even though utilizing nitric oxide (NO) as a gas medicine to repair diabetic wounds presents a promising strategy, controlling the NO release behavior in the affected area, which is vital for NO-based therapy, still remains a significant challenge. In this work, a copper-based metal–organic framework, namely, HKUST-1, has been introduced as a NO-loading vehicle, and a NO sustained release system with the core–shell structure has been designed through the electrospinning method. The results show that the NO is quantificationally and stably loaded in the HKUST-1 particles, and the NO-loaded HKUST-1 particles are well incorporated into the core layer of the coaxial nanofiber. Therefore, NO can be controllably released with an average release rate of 1.74 nmol L–1 h–1 for more than 14 days. Moreover, the additional copper ions released from the degradable HKUST-1 play a synergistic role with NO to promote endothelial cell growth and significantly improve the angiogenesis, collagen deposition as well as anti-inflammatory property in the wound bed, which eventually accelerate the diabetic wound healing. These results suggest that such a copper-based metal–organic framework material as a controllable NO-releasing vehicle is a highly efficient therapy for diabetic wounds.

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