The role of exosomes as oligonucleotide delivery system for managing α-synuclein in Parkinson’s disease: A systematic review of in vivo studies

Although Parkinson's disease (PD) is primarily idiopathic, genetic mutations-accounting for approximately 5%-15% of cases with regional variability-have prompted the development of gene expression modulators, such as oligonucleotides, to target and reduce alpha-synuclein (α-syn) accumulation. However, challenges in delivering these agents to the brain have limited their therapeutic potential. This study systematically reviews the use of exosomes as delivery systems for oligonucleotides aimed at reducing α-syn aggregation in PD. A comprehensive literature search was conducted using Scopus, Embase, OVID, and ISI Web of Science databases up to January 2022, targeting <i>in vivo</i> studies relevant to the subject. Of 904 initial records, five eligible studies were selected. Three utilized transgenic mouse models and two used induced models to simulate PD. All reported a reduction in α-syn aggregation in the midbrain-particularly in the substantia nigra-following treatment with exosome-delivered oligonucleotides. This reduction was associated with decreased neuronal death and improved motor function. No significant toxicity or immune response was reported. Exosome-mediated oligonucleotide delivery appears to be a promising approach to reduce α-syn aggregation, protect dopaminergic neurons, and improve motor symptoms in animal models of PD.