ObjectiveThis review comprehensively examined the emerging role of exosomes derived from periodontal ligament stem cells (PDLSC-Exos) in regenerative medicine and dentistry, with a particular focus on their therapeutic potential in periodontitis-a prevalent inflammatory disease characterized by the progressive destruction of periodontal tissues.MethodsAn initial search on Scopus, Web of Science, and PubMed using terms associated with exosomes (i.e., exosomes, exosomal, extracellular vesicles, and EVs) and periodontal ligament stem cells without any limitation of publication year and field of study was performed on October 31st, 2024.ResultsPDLSC-Exos demonstrated significant therapeutic efficacy in both bone and periodontal regeneration as well as various medical conditions through the enhancement of cellular proliferation, osteoblast differentiation, and the modulation of inflammatory responses. These exosomes function by regulating miRNA and activating essential signaling pathways, thereby facilitating periodontal/bone regeneration, angiogenesis, and tissue repair in disorders such as periodontitis, OTM, and skeletal bony defects. Furthermore, they exhibited anti-inflammatory properties, leading to improved outcomes under inflammatory conditions such as periodontitis, IBD, and MS. Moreover, PDLSC-Exos played a role in anti-microbial and anti-cancer interventions, demonstrating their diverse applicability.ConclusionThe cell-free nature of these therapeutic agents makes PDLSC-Exos a versatile and promising tool for regenerative medicine and immune system regulation. The cell-free nature of these therapeutic agents positions PDLSC-Exos as a promising and adaptable instrument for regenerative medicine and immune system modulation.Clinical relevancePDLSC-Exos offer a promising acellular therapy for periodontal regeneration, overcoming limitations of cell-based approaches by enhancing tissue repair, modulating inflammation, and improving clinical translation in regenerative medicine and dentistry.