HD is a neurodegenerative disorder caused by an autosomal dominant mutation in the huntingtin gene (HTT), leading to mutant protein aggregation, toxicity and neuronal cell death. microRNA (miRNA)-based gene therapies are a potential approach to reduce disease-causing protein in HD. We developed an engineered miHTT, delivered via AAV5 virus. AAV5-miHTT have demonstrated an efficient lowering in vitro and in vivo in the brain in different HD animal models. For efficacy in HD, brain-wide biodistribution (striatum, cortex) of the therapeutic miRNA is of crucial importance. Recently, EVs, including exosomes and microvesicles, have been identified as carriers of RNA species. Understanding how therapeutic miRNAs transfer between neuronal cells is relevant for delivery, translational studies, and biomarker discovery in gene therapies for brain disorders.