A composite hydrogel containing resveratrol-laden nanoparticles and platelet-derived extracellular vesicles promotes wound healing in diabetic mice

Diabetic wounds are difficult to heal because of persistent inflammation and limited angiogenesis. Resveratrol (RES) is an anti-inflammatory and antioxidant agent. Platelet-derived extracellular vesicles (PDEVs) are rich in growth factors and cytokines, which promote proliferation and angiogenesis. However, single drug treatment has limited efficacy and delivery efficiency. Bioengineering can improve the limited effect of single drugs by combining drugs and materials to obtain complementary or cooperative bioengineered drugs. In this study, gelatin methacrylate (GelMA) and silk fibroin glycidyl methacrylate (SFMA) were used to synthesize GelMA/SFMA composite hydrogels with suitable mechanical properties, swelling ratio and biodegradability. The composite hydrogel was used as a wound dressing for sustained drug release. RES was loaded into mesoporous silica nanoparticles (MSNs) to synthesize MSN-RES to enhance the release dynamic, and MSN-RES and PDEVs were combined with the composite hydrogels to form GelMA/SFMA/MSN-RES/PDEVs hydrogels. The GelMA/SFMA/MSN-RES/PDEVs had low cytotoxicity and good biocompatibility, inhibited macrophage iNOS expression, and promoted the tube formation by human umbilical vein endothelial cells (HUVECs) in vitro. In a diabetic mouse wound model, the GelMA/SFMA/MSN-RES/PDEVs hydrogels decreased the expression of pro-inflammatory factors TNF-α and iNOS, increased the expression of anti-inflammatory factors TGF-β1 and Arg-1, promoted angiogenesis, and accelerated wound healing. Interestingly, the GelMA/SFMA/MSN-RES/PDEVs hydrogels promoted the expression of extracellular purinergic signaling pathway-related CD73 and adenosine 2A receptor (A2A-R). Therefore, the GelMA/SFMA/MSN-RES/PDEVs hydrogels could be used as wound dressings to regulate the inflammation and angiogenesis of diabetic wounds and accelerate wound healing. STATEMENT OF SIGNIFICANCE: Drugs often fail to function because of a continuous oxidative stress microenvironment and inflammation. Here, a GelMA/SFMA hydrogel, with enhanced mechanical properties and liquid absorption ability, is proposed for sustained release of drugs. In addition to carrying platelet-derived extracellular vesicles (PDEVs) with pro-angiogenic effects, the hydrogels were also loaded with nanoparticle-encapsulated resveratrol with anti-inflammatory activities, aiming to reduce inflammation and oxidative stress in the wound microenvironment, such that the wound could receive proliferative repair signals to achieve sequential treatment and heal quickly. We also experimentally predicted that the regulatory mechanism of the GelMA/SFMA/MSN-RES/PDEVs in wound healing might be related to the extracellular purinergic signaling pathway.