The Role of Exercise-Derived Exosomes in the Rehabilitation of Neurological Disorders and Brain Injuries: A Systematic Review

Abstract

Context: Neurological disorders and brain injuries remain major causes of long-term disability, and currently available treatments provide only limited neurological recovery. Growing evidence indicates that exercise-derived extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transferring bioactive cargo that supports neural repair. This systematic review evaluated the therapeutic potential of exercise-derived EVs/exosomes and their associated microRNAs (miRNAs) in experimental models of neurological disorders and brain injuries. Evidence Acquisition: The review was designed and reported in accordance with the PRISMA 2020 Statement. PubMed, Scopus, and Web of Science were systematically searched for original animal studies published between 2020 and 2026. Two reviewers independently performed study selection, data extraction, and methodological quality assessment using the SYRCLE Risk of Bias tool. Owing to substantial methodological heterogeneity, quantitative pooling was not feasible; therefore, the evidence was synthesized narratively. Results: Sixteen preclinical studies were included. Overall, the methodological quality was acceptable, although several SYRCLE domains were rated as unclear because of insufficient reporting. Across multiple neurological disease models, exercise-derived EVs/exosomes consistently improved neurological outcomes by reducing neuronal apoptosis, neuroinflammation, and oxidative stress while enhancing neuroregeneration, angiogenesis, synaptic plasticity, and blood-brain barrier integrity. These effects were associated with the modulation of key exosomal miRNAs, particularly miR-126, miR-124, and miR-484, along with activation of multiple signaling pathways, including PI3K/Akt, STAT3, MAPK, TGF-β/SMAD, mTOR, NF-κB, and p38. Discussion: Available preclinical evidence supports exercise-derived EVs/exosomes as promising therapeutic mediators for neurological rehabilitation. Nevertheless, methodological heterogeneity and inconsistent procedures for EV/exosome isolation and characterization remain major barriers to clinical translation. Future studies should adopt standardized experimental methodologies and validate these findings in rigorously designed clinical trials.