Extracellular vesicle therapies in regenerative endodontic procedures: A systematic review and meta-analysis of in vivo studies

Objective To systematically review and quantitatively synthesize in vivo evidence on extracellular vesicle (EV)–based therapies for regenerative endodontic procedures, focusing on mineralization and angiogenesis outcomes. Methods We conducted a systematic review and meta-analysis of in vivo preclinical dentoalveolar/regenerative endodontic models comparing EV-based interventions (exosomes/microvesicles/apoptotic bodies), alone or with scaffolds, versus control conditions. Searches were performed in Web of Science Core Collection and Scopus from inception to 31 December 2025, with reference screening. Random-effects meta-analyses pooled standardized mean differences (SMDs) for mineralization and angiogenesis; heterogeneity was assessed using I 2 . Risk of bias was evaluated using the Systematic Review Centre for Laboratory animal Experimentation tool. Results Twenty-one studies met inclusion criteria; seven were included in the mineralization meta-analysis and five in the angiogenesis meta-analysis. EV-based therapies significantly increased mineralization versus controls (SMD = 6.43; 95% confidence interval (CI) [3.13–9.73]; I 2 = 91%) and angiogenesis (SMD = 7.89; 95% CI [3.94–11.85]; I 2 = 82%). Subgroup analyses suggested stronger effects for EVs derived from dental pulp stem cells, stem cells from human exfoliated deciduous teeth, and stem cells from apical papilla. Risk of bias was predominantly unclear due to limited reporting of randomization and blinding. Considerable heterogeneity, small numbers of pooled studies, and variability in EV isolation, characterization, dosing, and outcome assessment limit generalizability and translation. Conclusions EV-based therapies enhance mineralization and angiogenesis in preclinical regenerative endodontic models, with dental stem cell–derived EVs showing the greatest apparent potential. However, effect sizes should be interpreted cautiously given very high heterogeneity and methodological/reporting limitations. PROSPERO registration : Centre for Reviews and Dissemination 420251107328.