Therapeutic Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles as a Cell-Free Approach in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis of Preclinical Studies.

BACKGROUND: Autism Spectrum Disorder (ASD) is an intricate neurodevelopmental condition distinguished by challenges in social interaction, repetitive behavioral patterns, and neuroinflammation, with limited effective treatments. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) offer a promising cell-free therapy due to their immunomodulatory and regenerative properties. This study evaluates their therapeutic efficacy in preclinical ASD models. METHODS: Following PRISMA guidelines, we conducted a systematic review and meta-analysis, searching PubMed, Embase, Scopus, and Web of Science. The SYRCLE tool assessed risk of bias. Standardized mean difference (SMD) was calculated using a random-effects model to evaluate MSC-EV effects on sociability, repetitive behaviors, and inflammatory cytokines. Subgroup analysis, sensitivity analysis, and publication bias assessment addressed heterogeneity. RESULTS: Five studies (2018-2024) were included. MSC-EV-treated mice showed significant improvements in sociability (SMD =1.34, 95% CI:0.68-2.76), reduced repetitive behaviors (SMD =-1.12, 95% CI:-0.65 to -1.59), and modulated neuroinflammation, with decreased pro-inflammatory cytokines (IL-1, SMD = -2.28, 95% CI:-0.33 to -4.24 and TNF-a, SMD = -1.22, 95% CI:-0.47 to -1.97 and IL-6, SMD = -1.03, 95% CI:-0.38 to -1.68) and increased IL-10 (SMD =0.58, 95% CI:0.03 to 1.13). Subgroup analysis indicated umbilical cord- and adipose-derived MSC-EVs had superior efficacy. CONCLUSION: MSC-EVs demonstrate significant therapeutic potential in preclinical ASD models by improving core symptoms and modulating inflammation. However, limited studies and heterogeneity highlight the need for standardized protocols and further preclinical research to facilitate clinical translation.