Polyelectrolyte complex micelles embedded in hyaluronic acid gels enable local, targeted miR-92a inhibition to...

Diabetic wounds are characterized by various cellular deficiencies, particularly insufficient angiogenesis. MicroRNA 92a (miR-92a) is a known factor in diabetic wounds that perpetuates non-healing wound phenotypes by inhibiting angiogenesis. Therefore, its local inhibition at wound sites has therapeutic potential. To achieve this, we combine a nanoparticle formulation of polyelectrolyte complex micelles (PCMs) delivering miR-92a inhibitors with a hyaluronic acid (HA) gel formulation suitable for topical application to wound sites. The nanoparticles, formed by polyelectrolyte complexation of poly(ethylene glycol)-block-poly(L-lysine) with RNA cargo, are functionalized with targeting peptides against vascular cell adhesion molecule 1 (VCAM-1) to improve affinity for inflamed endothelial cells. We demonstrate effective PCM encapsulation and controlled release from gel formulations in vitro and in vivo. These PCMs are taken up in vivo by endothelial cells and exert functional transcriptional effects on miR-92a and its downstream targets. Furthermore, our composite PCM-gel formulation significantly accelerates wound closure in diabetic mouse models and improves angiogenesis, consistent with the known role of miR-92a inhibition in vascular regeneration. This work demonstrates a highly translatable formulation for improved wound healing, and lays the framework for modular nanoparticle-gel systems that can achieve local, cell-targeted RNA delivery.