Met@MPDA rejuvenates BMSC energy metabolism to promote bone regeneration in semaglutide-treated obese periodontitis

Obesity is closely linked to periodontitis development. Although semaglutide is increasingly used to manage obesity, its effects on alveolar bone repair in periodontitis are not well understood. In a mouse model of obesity-related periodontitis, we found that obesity exacerbates alveolar bone loss in an inflammatory setting. Semaglutide treatment slightly reduced periodontal inflammation and osteoclast markers but did not improve osteogenesis or regenerate alveolar defects. Transcriptomic analysis revealed increased fatty-acid uptake but suppressed AMPK signaling and reduced fatty-acid oxidation (FAO) in inflamed alveolar bone of obese mice. In vitro , macrophage FAO was largely unaffected by inflammation or semaglutide, while FAO in bone marrow–derived mesenchymal stem cells (BMSCs) was significantly reduced, impairing osteogenic differentiation. To tackle metabolic and osteogenic issues, we created a metformin-loaded mesoporous polydopamine system (Met@MPDA) that acts as an AMPK agonist. Met@MPDA is absorbed by BMSCs, restoring cellular energy and promoting alveolar bone regeneration in periodontitis. While semaglutide provides anti-inflammatory benefits in obesity-related periodontitis, it falls short in boosting bone regeneration due to metabolic issues in BMSCs. Thus, Met@MPDA's sustained metformin delivery could enhance bone regeneration in these cases. Obesity aggravates periodontitis by amplifying inflammatory burden and accelerating alveolar bone loss. In obese mice, systemic semaglutide attenuates inflammation, yet bone regeneration remains suboptimal. Met@MPDA-Gel enhances osteogenesis by rewiring BMSC energy metabolism to favor bone formation. Importantly, the combination synchronizes anti-inflammatory efficacy with anabolic bone repair, thereby mitigating periodontal destruction in the context of obesity. Collectively, these findings suggest that, alongside semaglutide-based obesity management, Met@MPDA-Gel represents a promising adjunctive therapy for obesity-associated periodontitis.