Salivary Extracellular Vesicle Proteome as a Molecular Bridge Between Periodontitis and Neurodegeneration: Mechanisms, Biomarkers, and Therapeutic Opportunities

Periodontitis is a chronic inflammatory condition associated with systemic inflammation and an increased risk of neurodegenerative disorders. Salivary extracellular vesicles (EVs) carry molecular cargo in an enclosed form and could serve as a non-invasive platform to explore communication between the oral system and the brain. The review analyzes the current evidence on salivary EV proteomes, their mechanistic links to neurodegeneration, and their biomarker potential. This is a narrative review, and PRISMA-2020 reporting was used as a transparency tool only. The following keywords were used to search the databases PubMed/MEDLINE, Scopus, and Web of Science for publications from 2009 to 2026: periodontal disease, periodontitis, salivary EVs, proteomics, neuroinflammation, blood-brain barrier (BBB) dysfunction, and neurodegeneration. After applying the structured screening and eligibility assessment procedure, 112 studies were included in the qualitative synthesis. Synthesized evidence suggests that cytokines, complement proteins, proteases, acute-phase mediators, and oxidative-stress signals are produced during periodontal inflammation and could be detected in salivary EV cargo. These molecular signals converge on TLR2/TLR4-NF-κB, the NLRP3 inflammasome, HMGB1-RAGE, complement C3/C1q, MMP-9-mediated BBB disruption, IL-1β/IL-6/TNF-α signaling, and oxidative stress-mitochondrial injury, potentially leading to endothelial dysfunction, BBB permeability, microglial activation, and neuronal injury. The results indicate that salivary EVs are not only biomarkers but are biologically active, suggesting a possible molecular basis for the link between periodontal inflammation and neurodegenerative processes. This review incorporates the latest data related to salivary EV proteomics, periodontal inflammation, BBB dysfunction, neuroimmune signaling, and biomarker development, with a focus on EV engineering and other emerging strategies as potential avenues for future diagnosis and therapy.