Extracellular vesicles at the periodontal immune–regenerative interface: coupled mechanisms and translational challenges

Abstract

Periodontitis is a chronic immune-inflammatory disease in which dysbiotic microbial communities and sustained host responses disrupt the gingiva, periodontal ligament (PDL), cementum, and alveolar bone. Because these tissues form an integrated attachment apparatus, effective regeneration requires coordinated control of inflammation and reconstruction of soft and mineralized tissues. Extracellular vesicles (EVs) function as intercellular mediators at this immune–regenerative interface by transferring proteins, lipids, and nucleic acids among immune, stromal, vascular, and bone-remodeling cells. This review synthesizes how EVs connect immune reprogramming, microenvironmental remodeling, and tissue-specific repair in periodontitis. Across experimental studies, EVs regulate macrophage activation and T-cell balance, modulate inflammatory, oxidative, vascular, and osteoclastogenic signaling, and influence the survival, migration, and differentiation of gingival, PDL, cementoblast, and osteoblast-lineage cells. Together, these actions link inflammatory resolution to the cellular processes required for gingival healing, alveolar bone formation, cementogenesis, and re-establishment of the PDL–cementum–bone interface. EV activity is shaped by donor-cell identity and physiological state, culture and separation procedures, molecular cargo, dose, recipient cell, and disease context; this context dependence explains why different EV preparations can produce reparative or pathogenic responses. Cargo engineering, surface modification, and biomaterial-assisted local delivery offer routes to enhance potency, cellular interaction, and retention within periodontal defects. Translation now depends on defining reproducible EV products, establishing mechanism-linked potency assays, standardizing dose and quality control, and evaluating safety and function in disease-relevant models. Current evidence is predominantly preclinical and indicates that process-defined EV preparations can link inflammatory resolution with tissue reconstruction as adjuncts to infection control and established periodontal regenerative procedures.