Biological Functions and Applications of Exosomes from Periodontal Ligament Stem Cells.

Periodontal regeneration requires the reconstruction of root cementum, periodontal ligament, and alveolar bone, which are frequently disrupted by periodontitis, trauma, and other inflammatory conditions. Although periodontal ligament stem cells (PDLSCs) have been considered promising for periodontal tissue engineering because of their multipotency, self-renewal capacity, and immunomodulatory activity, direct cell-based therapy still faces various limitations, including donor variability, culture-related changes, delivery difficulties, and safety concerns. Exosomes and small extracellular vesicles derived from PDLSCs have therefore attracted attention as potential cell-free mediators of PDLSC paracrine activity. PDLSC-derived exosomes carry bioactive molecules, including proteins, lipids, messenger RNAs, and microRNAs, and can influence recipient cell behavior in periodontal and bone regenerative environments. In vitro and preclinical animal studies indicate that PDLSC-derived exosomes are involved in osteogenesis, periodontal attachment repair, cementogenesis, angiogenesis, mechanotransduction, cell proliferation/survival, and immune regulation. Their biological effects are closely related to the condition of their parental PDLSCs, their cargo, and the exosome isolation and characterization methods used. In this review, we summarize recent findings on the isolation strategies used, biological functions of, and therapeutic potential of PDLSC-derived exosomes, with particular focus on protein cargo, proteomic signatures, proteoform-related interpretation, and microRNA-mediated regulation. We also discuss current challenges in exosome isolation, characterization, delivery, stability, and reporting standards for future periodontal regenerative applications. The findings discussed throughout are preclinical, and their translation to clinical settings remains to be explored.