Abstract
Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .