Mesenchymal stem/stromal cell-based therapies for autism spectrum disorder: emerging evidence and clinical prospects

Abstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with rising global prevalence. Current management strategies predominantly address behavioral symptoms rather than core neurobiological dysfunctions, highlighting an unmet need for mechanism-targeted interventions. Main body This review comprehensively evaluates the therapeutic potential of mesenchymal stem/stromal cell (MSC)-based therapies for ASD. We discuss the multi-faceted mechanisms through which MSCs and their secretomes (particularly MSC-EVs or MSC-exos) may ameliorate ASD pathophysiology, including modulation of neuroinflammation via anti-inflammatory cytokine and adenosine signaling, promotion of neurogenesis and synaptic plasticity through neurotrophic factors (e.g., BDNF, GDNF), restoration of gut-brain axis communication, and enhancement of cerebral angiogenesis via VEGF. We synthesize a decade of preclinical evidence (2015–2025) from various ASD animal models (e.g., BTBR, VPA-induced, MIA, Shank3B KO), detailing improvements in social behavior, repetitive actions, and cognitive function following MSC or MSC-derived product administration via routes such as intravenous, intranasal, or intracerebroventricular delivery. Furthermore, we analyze all registered early-phase clinical trials (Phase I and II, n = 9 as of March 2026), comparing different MSC sources, their safety profiles, and preliminary efficacy outcomes. Key challenges are examined, including heterogeneity in trial design, small sample sizes, the predominance of open-label studies, and the gap between promising preclinical results and established clinical translation. Conclusions MSC-based therapy represents a transformative, pathophysiology-informed strategy for ASD. While preclinical and early clinical data are encouraging, significant hurdles remain in standardization, dose optimization, and demonstration of long-term efficacy and safety. We emphasize the necessity for rigorous, large-scale randomized controlled trials (RCTs) to advance this promising therapeutic approach toward clinical application. Graphical Abstract