RES NPs/GelMA Sustained-Release Cryogel Modulates Macrophage Arachidonic Acid Metabolism and Angiogenic Microenvironment Promoting Diabetic Wound Healing

Abstract

Refractory chronic diabetic wounds severely impair quality of life. Their delayed healing is mainly driven by impaired angiogenesis and persistent inflammation caused by infection and excessive ROS. Resveratrol (RES) has anti-inflammatory and pro-angiogenic effects, but its clinical use is limited by poor solubility and low bioavailability. Here, we developed a dual-mechanism sustained-release system for RES to promote diabetic wound healing. RES was converted into nanoparticles (RES NPs) to improve cellular uptake and bioavailability, then encapsulated in GelMA cryogel microspheres (CMS) for injectable, sustained release. This system downregulated NF-κB signaling, reduced ROS, and suppressed pro-inflammatory cytokines and COX2, thereby inhibiting arachidonic acid metabolism and promoting macrophage polarization from M1 to M2. Meanwhile, AMPK activation restored endothelial cell function, enhanced angiogenesis, and supported new vessel formation. Overall, this strategy accelerated high-quality wound repair in diabetic conditions.