<p>Diabetes mellitus (DM) exacerbates periodontitis as the high-glucose (HG) environment aggravates local inflammation and periodontal bone resorption. Restoring periodontal homeostasis and promoting periodontal bone repair/regeneration are major challenges for the treatment of diabetic periodontitis. This study introduces antler stem cell-derived exosomes (AnSC-exos) as a potent therapeutic for treating diabetic periodontitis via leveraging the shared cranial neural crest cell (CNCC) origin of antlers and periodontal tissues. Using a rat model of diabetic periodontitis, we demonstrate that AnSC-exos effectively alleviate tissue abnormalities and alveolar bone destruction and resorption in periodontitis under DM conditions; the outcome was significantly more potent than human bone marrow mesenchymal stem cell exosomes (hBMSC-exos). Mechanistically, AnSC-exos exhibited dual regenerative actions: (1) restoring the osteogenic ability of resident MSCs by not only reversing high glucose (HG)-induced suppression of proliferation and migration, but more importantly, enhancing cell survival, reducing cell death, and strengthening differentiation toward osteogenic lineages under HG conditions; and (2) attenuating inflammation through potently scavenging excessive ROS production induced by HG, and inhibiting HG-mediated p65 nuclear translocation, thereby leading to a reduced M1/M2 macrophage ratio. In conclusion, the superior efficacy of AnSC-exos highlights their tissue-specific regenerative advantage and establishes AnSC-exos as a promising cell-free therapy that simultaneously targets osteogenic impairment and ROS-driven inflammation in diabetic periodontitis. Further characterization of active components within the exosomes holds significant promise for developing effective clinical treatments for diabetic periodontitis.</p>