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Yet, their efficacy is constrained by the need for invasive delivery, poor central nervous system (CNS) penetration, inefficient cellular uptake and rapid clearance. Here, we developed neural stem cell\u2010derived extracellular vesicles (NSC\u2010EVs) as natural carriers to enhance CNS targeting and therapeutic efficacy of ASO\u2010based treatments for ALS. Using a passive loading method, therapeutic ASOs were efficiently associated with NSC\u2010EVs (NSC\u2010EV\u2010ASO). Compared with free ASOs, NSC\u2010EVs\u2010 ASOs exhibited markedly enhanced neuronal uptake in vitro and increased CNS accumulation and neuronal localization in vivo following intracerebroventricular, intranasal, or intravenous administration. Functionally, NSC\u2010EV\u2010ASOs reduced the mutant SOD1 protein expression and the pathogenic hexanucleotide repeats in the\n                    <jats:italic>C9orf72<\/jats:italic>\n                    loci in ALS cellular models. In the ALS mouse model, intranasal administration of NSC\u2010EV\u2010ASOs more efficiently delayed disease onset, improved motor performance, preserved motor neurons and attenuated astrocyte activation during the study period compared with free ASOs. These findings provide proof\u2010of\u2010concept evidence supporting the potential of NSC\u2010EV as a promising platform that not only enhances CNS delivery of ASOs but also contributes to overall therapeutic activity, offering a synergistic strategy to advance nucleic acid therapeutics for ALS and potentially other neurological diseases.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70370","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:08:57Z","timestamp":1789495737000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural Stem Cell\u2010Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1646-5964","authenticated-orcid":false,"given":"Yaochao","family":"Zheng","sequence":"first","affiliation":[{"name":"Regenerative Bioscience Center, Department of Animal 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