Extracellular Vesicles and Exosomes in Periodontal Regeneration: From Biological Signalling to Cell Free Therapy

Abstract Extracellular vesicles (EVs) are membrane bound particles released by cells that transport proteins, lipids, messenger RNA, microRNA, and other regulatory molecules. In periodontics, they have attracted attention because they can influence both the inflammatory phase of wound healing and the subsequent formation of periodontal ligament, cementum, and alveolar bone. Their biological effect is source dependent: vesicles released by periodontal pathogens and activated host cells may intensify inflammation, whereas vesicles derived from mesenchymal stromal cells and dental stem/stromal cells have shown anti-inflammatory, pro angiogenic, and osteogenic activity in experimental models. EV-based therapy is appealing as a cell free approach that may reproduce selected paracrine effects of stem cell therapy without administering viable cells. Local delivery through collagen matrices, injectable hydrogels, and multifunctional scaffolds may improve retention in periodontal defects and protect vesicles from rapid clearance. Recent investigations have also explored parent cell preconditioning, engineered vesicles, and apoptotic extracellular vesicles to improve therapeutic potency. Despite encouraging preclinical results and limited early human evidence, routine clinical application remains premature. Product heterogeneity, inconsistent isolation and dose reporting, uncertain biodistribution, incomplete long term safety data, and the absence of adequately powered randomized clinical trials remain major barriers. This narrative review presents a complete account of EV terminology, sources, mechanisms, delivery strategies, current evidence, clinical relevance, and translational requirements in periodontal regeneration.