Efficacy of dental stem cell–derived exosomes for pulp regeneration: a systematic review of clinical, animal, and in vitro studies

Exosomes derived from dental stem cells (DSC-Exos) are nanovesicles (~ 30–150 nm) that mediate angiogenesis, odontoblastic differentiation, and immune regulation, positioning them as promising cell-free candidates for pulp–dentin regeneration. This PROSPERO-registered systematic review evaluated the regenerative potential of DSC-Exos and the methodological factors influencing outcomes. A comprehensive search of PubMed, Scopus, Web of Science, and Embase was conducted through July 2025; risk of bias was assessed using RoB 2.0, SYRCLE, and QUIN tools. Thirteen studies fulfilled the inclusion criteria, most of which employed exosomes derived from human dental pulp stem cells, stem cells from human exfoliated deciduous teeth and stem cells from the apical papilla. DSC-Exos consistently promoted cell proliferation and migration while upregulating odontogenic (DSPP, DMP1) and angiogenic (VEGF, CD31) markers. Animal models demonstrated vascularized pulp-like tissue and organized tubular dentin formation, significantly enhanced by donor-cell preconditioning and biodegradable carriers. Mechanistic investigations linked these outcomes to noncoding RNAs and signaling axes like miR-26a/TGF-β and circ_0003057/EIF4A3/ANKH. A 24-month clinical pilot confirmed restored pulp sensitivity without safety concerns. Nevertheless, the overall certainty of evidence remains moderate to low, mainly due to substantial methodological heterogeneity, limited sample sizes and insufficient reporting of critical parameters such as exosome characterization, dosing strategies and operator calibration. Collectively, the findings indicate that DSC-Exos represent a high-potential biomimetic strategy for pulp–dentin regeneration; however, standardized characterization protocols in line with MISEV guidelines, dose harmonization and well-designed long-term controlled clinical trials are essential before cell-free endodontic therapies can be reliably incorporated into clinical practice.