M2 macrophage-derived extracellular vesicle/polydopamine hydrogel attenuates diabetic periodontitis-induced bone loss via the NEK7/NLRP3/IL−1β pathway

The pathological progression of diabetic periodontitis is closely associated with macrophage functional imbalance induced by a high-glucose environment. High glucose significantly upregulates IL-1β and other pro-inflammatory factors by activating NLRP3 inflammasomes in macrophages, exacerbating periodontal tissue inflammation and suppressing osteoblast activity. Extracellular vesicles derived from M2-type macrophages (M2-EVs) effectively inhibit NLRP3 inflammasome activation and ameliorate macrophage polarisation imbalance through their natural inflammatory targeting affinity and miR-23a-3p-mediated negative regulation of NEK7. The M2-EVs/PDA/GelMA hydrogel developed in this study enables controlled release via a dynamic network structure, significantly reducing NLRP3 and IL-1β expression in periodontal tissues while promoting bone marrow stromal cell (BMSC) osteogenic differentiation through reparative macrophage-mediated secretion of osteoinductive factors, ultimately achieving periodontal bone repair and regeneration. This strategy establishes a novel multifunctional biomaterial platform for diabetic periodontitis treatment by integrating immune modulation and bone regeneration mechanisms, demonstrating significant potential for clinical translation.