Garlic-Derived Exosome-Like Nanovesicles: A Promising Natural Nanotherapy for Periodontitis via PHGDH/PI3K/AKT-Mediated Metabolic and Inflammatory Regulation

Background: Periodontitis is a chronic inflammatory disease that leads to alveolar bone loss, with a complex pathogenesis closely associated with excessive local inflammation and metabolic dysregulation in periodontal tissues. Unfortunately, effective therapeutic strategies targeting inflammation and improving cellular metabolism remain lacking. Garlic-derived exosome-like nanovesicles (GaELNs), as a natural therapeutic agent, have demonstrated significant therapeutic effects in conditions such as colitis, liver dysfunction, osteoarthritis, and adipose tissue inflammation, yet their potential in treating periodontitis has not been explored. Methods: In this study, GaELNs were extracted using a simplified and rapid method and characterized for their morphology and concentration. Metabolomic analysis was conducted to determine the bioactive components within GaELNs. In vitro experiments using human gingival fibroblasts assessed GaELNs' cellular uptake, effects on cell proliferation, migration, VEGF expression, and their ability to attenuate lipopolysaccharide-induced oxidative stress and pro-inflammatory cytokine expression. Additionally, a mouse periodontitis model was employed to evaluate the in vivo effects of GaELNs on local inflammation and bone resorption. Results: GaELNs exhibited typical exosome-like characteristics with sufficient concentration and high batch-to-batch reproducibility. Metabolomic analysis revealed that GaELNs are enriched with bioactive components possessing anti-inflammatory, antioxidative, and regenerative properties. In vitro, GaELNs were efficiently internalized by human gingival fibroblasts, significantly enhancing their proliferation, migration, and VEGF expression, while markedly reducing LPS-induced oxidative stress and pro-inflammatory factor expression. In the mouse periodontitis model, local administration of GaELNs significantly reduced gingival inflammation and alveolar bone resorption. These therapeutic effects were mediated by upregulation of PHGDH, activation of the PI3K/AKT signaling pathway, increased expression of mTOR and Nrf2, and inhibition of NF-κB activity, which together contributed to improved mitochondrial function and metabolic reprogramming under inflammatory conditions. Conclusion: GaELNs demonstrate potent anti-inflammatory, antioxidative, and metabolism-enhancing properties, offering significant therapeutic potential for the treatment of periodontitis by modulating the PHGDH/PI3K/AKT pathway.