Exosome-functionalized scaffolds for bone regeneration: a systematic review and meta-analysis

Abstract Background Exosome/small extracellular vesicle (sEV)-functionalized scaffolds represent a promising cell-free strategy for bone regeneration by combining biomaterial structural support with sustained EV-mediated osteogenic, angiogenic, and immunomodulatory signaling. Methods A PRISMA 2020–compliant systematic review and meta-analysis was conducted, prospectively registered in the PROSPERO database (registration number: CRD420251248297), to synthesize preclinical evidence from animal bone defect models and complementary in vitro studies published between January 1, 2010, and August 28, 2025. PubMed/MEDLINE, Scopus, Web of Science Core Collection, Embase, and Google Scholar were searched for English-language preclinical studies evaluating EV/sEV-functionalized scaffolds, including studies describing these vesicle preparations as exosomes. Animal bone defect models were considered for quantitative synthesis, while in vitro studies provided complementary mechanistic evidence. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the SYRCLE tool. Random-effects meta-analyses pooled standardized week-8 outcomes as Hedges’ g. Results Forty-one studies were included in the qualitative synthesis and 24 were eligible for the meta-analysis. Most investigations combined in vitro and in vivo experiments, were conducted in China, and used rat models, particularly critical-sized calvarial defects. Mesenchymal stem cell-derived exosome/sEV preparations, frequently described as exosomes by the original studies, predominated, particularly those derived from bone marrow MSCs. Physical adsorption and hydrogel encapsulation were the most commonly reported incorporation strategies. At week 8, exosome/sEV-functionalized scaffolds significantly improved bone volume fraction (BV/TV; 17 studies; standardized mean difference (SMD) [Hedges’ g]=6.00, 95% CI 4.19–7.81) and bone mineral density (BMD; 7 studies; Hedges’ g=5.27, 95% CI 2.95–7.60), although substantial heterogeneity remained. Conclusion Exosome/sEV-functionalized scaffolds were associated with improvements in quantitative radiological outcomes, with complementary qualitative evidence from histological assessments. However, interpretation of these findings is limited by methodological variability and heterogeneity among preclinical studies. Standardized reporting, improved randomization/blinding, and large-animal validation are needed to refine effect estimates before clinical translation.