Understanding exosomes in regenerative dentistry

BACKGROUND: Regenerative dentistry is shifting from cell-based strategies to cell-free biologics capable of orchestrating intricate tissue repair. Exosomes, nanosized extracellular vesicles carrying bioactive molecular payloads, have emerged as central modulators of intercellular communication. This review aimed to offer a comprehensive synthesis of exosome-based regenerative processes across oral and craniomaxillofacial (CMF) tissues. METHODS: A structured literature review was performed utilizing PubMed, Scopus, and Web of Science databases without time restriction. Eligible studies included in vitro, in vivo, and clinical investigations assessing exosome-based mechanisms, molecular signaling pathways, and bioengineering approaches in regenerative dentistry. RESULTS: Exosomes derived from stem cells, immune cells, and dental tissues showed multifaceted regenerative impacts across periodontal, endodontic, orthodontic, and CMF applications. Mechanistically, exosomes mediated osteogenesis, angiogenesis, immune regulation, oxidative stress, and stem cell recruitment through central pathways, such as the PI3K/AKT, MAPK/ERK, Wnt/β-catenin, TGF-β/BMP, and NF-κB. They enhanced macrophage polarization toward anti-inflammatory phenotypes, restored osteoclast-osteoblast homeostasis, enhanced angiogenesis, and preserved mitochondrial homeostasis. In regenerative endodontics, exosomes enhanced cell viability, decreased apoptosis, and improved odontogenic differentiation and neurovascular coupling. In orthodontic and CMF regeneration, they coordinated mechanotransduction, osteogenesis, and angiogenesis. Bioengineering approaches, such as scaffold-mediated platforms, preconditioning, and genetic modification, further improved exosome stability, targeting, and treatment efficacy. CONCLUSION: Exosomes represent a versatile and robust cell-free treatment approach capable of orchestrating intricate oral tissue regeneration. Despite promising preclinical evidence, challenges associated with standardization, scalability, and clinical validation must be addressed to allow translation in routine dental practice.