Bio inspired assessment of titanium-organic framework and exosome-constructed p-Synephrine carriage: pursuing the PI3K/mTOR pathway in a simulated periodontitis.

Periodontitis, a chronic inflammatory disease, is driven by bacterial infection and oxidative stress, leading to tissue destruction and potential tooth loss. This study investigates the anti-inflammatory and antioxidant potential of p-Synephrine and enhanced delivery through NH2-MIL-125 and exosomes derived from dental pulp stem cells (DPSCs). Primary Normal Human Gingival Keratinocytes (PCS) and Gingival Fibroblasts (HGF) were divided into eight groups, including controls, induction with LPS, and treatments with NH2-MIL-125, exosomes, free p-Synephrine, p-Synephrine-loaded NH2-MIL-125 (P-SYN-NH2-MIL-125), p-Synephrine-loaded exosomes (P-SYN-Exo), and dexamethasone as a reference drug. Pro-inflammatory cytokines (IL-4, IL-6, TNF-α) and pathway markers (PI3K and mTOR) were quantified using ELISA kits, while antioxidant enzyme activities (GPx, SOD, and TAC) were assessed using colorimetric assays. Results showed that p-Synephrine loaded into NH2-MIL-125 reduced inflammation markers and enhanced antioxidant defenses by increasingof GPx, SOD, and TAC concentrations. Among all treatments, p-Synephrine-loaded exosomes (P-SYN-Exo) demonstrated the most significant results, showing the highest increase in antioxidant markers GPx, SOD, and TAC, alongside a pronounced reduction in pro-inflammatory cytokines IL-4, IL-6, and TNF-α. Furthermore, p-Syn-Exo exhibited the most marked decrease in signaling pathway markers PI3K and mTOR. NH2-MIL-125 and exosomes amplified these effects through controlled release and improved bioavailability, demonstrating superior reductions in TNF-α, IL-4, and IL-6 and increased antioxidative stress markers. These findings highlight p-Synephrine, particularly when delivered via NH2-MIL-125 and exosomes, as a promising adjunctive treatment for periodontal inflammation and oxidative stress.