Beyond the hype: re-evaluating efficacy metrics and modeling rigor for MSC-EVs-based therapy in acute brain injury

Acute brain injuries (ABI), such as traumatic brain injury, stroke, hypoxia-induced brain injury, and cardiac arrest, are critical and life-threatening conditions that contribute to substantial mortality and long-term disability. Despite extensive translational efforts, no effective therapy has improved long-term functional outcomes, highlighting a critical unmet need. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising cell-free therapeutic platform, offering multifaceted repair capabilities. This review synthesizes current evidence supporting the neuroprotective effects of MSC-EVs, which operate through synchronized immunomodulation, anti-apoptotic signaling, enhancement of neurogenesis, and stimulation of angiogenesis. We further delineated the fundamental EVs biology, including biogenesis pathways, spatiotemporal biodistribution, and blood-brain barrier (BBB) trafficking mechanisms that underpin therapeutic efficacy. Collectively, we established MSC-EV cargo as a strategic solution to unmet neuroprotective needs while mapping clinical translation roadmaps to accelerate the rational development of regenerative neurotherapeutics.