Viola Yedoensis Makino‐Derived Exosome‐Like Nanovesicles‐Loaded Adhesive Promotes Diabetic Fracture Healing via Anti‐Inflammatory Properties

Fracture management in patients with diabetes mellitus presents a significant clinical challenge, often resulting in nonunion or delayed fracture healing due to dysregulation of macrophage polarization and a persistent inflammatory microenvironment. While traditional internal fixation provides fracture stabilization, it exhibits limited ability to modulate the inflammatory microenvironment, thereby limiting bone regeneration. In this study, a bioadhesive hydrogel (DPC-3) incorporating Viola yedoensis Makino-derived exosome-like nanovesicles (VDNPs) is developed to enhance fracture healing through localized immunomodulation. The hydrogel, synthesized via a Schiff base reaction between polyacrylamide (Pam), dialdehyde starch, and 30% oxidized chondroitin sulfate, exhibited robust tissue adhesion, mechanical stability, and sustained VDNPs release. Mechanistically, VDNPs facilitated M2 macrophage polarization through downregulation of the NF-κB signaling pathway, mitigating inflammation and promoting osteogenesis. In a diabetic femoral fracture model, the DPC-3/VDNPs hydrogel significantly accelerated bone regeneration compared to conventional treatments, evidenced by enhanced bone mineral density, volume fraction, and trabecular thickness, alongside histological analyses demonstrating increased osteogenesis and collagen deposition. Overall, these findings highlight the potential of the DPC-3/VDNPs hydrogel as a promising therapeutic strategy for improving diabetic fracture healing outcomes by integrating mechanical support with biological activity derived from natural sources.