Introduction: Neurodegenerative disorders like Alzheimer\\\'s disease (AD), Parkinson\\\'s disease (PD), and multiple sclerosis (MS) lack effective treatments. Exosomal microRNAs (miRNAs), small vesicle-derived regulators of gene expression, have emerged as therapeutic agents for disease treatment due to their ability to cross the blood-brain barrier . To systematically review therapeutic applications of exosomal miRNAs in preclinical models of AD, PD, and MS, identifying key miRNAs, mechanisms of action, and therapeutic outcomes. Data Sources: Literature search in PubMed, Web of Science, and Scopus (January 2014-March 2024) using combinations of exosome, microRNA, and neurodegenerative disease terms. Study Selection: Studies investigating therapeutic applications of exosomal miRNAs in AD, PD, or MS using disease models, examining specific miRNAs and their therapeutic effects, published in English. Reviewers screened studies using predefined criteria. Data Extraction: Data extracted using standardized forms encompassing study characteristics, exosome sources, microRNA information, and outcomes. Quality assessed using modified SYRCLE and JBI tools. Results: Forty studies were included: AD (n = 20), PD (n = 11), and MS (n = 9). Mesenchymal stem cell-derived exosomes were predominant (55%). In AD, miR-29 and miR-124 targeted amyloidogenesis via BACE1 and NLRP3 pathways, with cognitive improvement in 55% of studies and 40-50% Aβ reduction. In PD, miR-7 and miR-100a-5p modulated autophagy and oxidative stress, providing neuroprotection in 72% of studies. In MS, miR-219 and miR-23a promoted remyelination in 67% of studies with enhanced oligodendrocyte differentiation and reduced inflammatory markers by 30-60%. Conclusion: Exosomal miRNAs demonstrate significant therapeutic potential for neurodegenerative diseases. Their ability to target pathological pathways positions them as promising candidates for clinical translation.

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