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As treatment for CNS disorders is primarily palliative, the underlying causes of disease progression are not addressed through conventional pharmacologic therapies. Gene therapy has the potential to address these root causes of disease progression; however, many of the vectors used in gene therapy (e.g., adeno-associated viruses (AAVs)) have limitations such as immunogenicity, low cargo capacity, and crossing the blood-brain barrier (BBB). These limitations have led to significant progress in the development of non-viral gene delivery systems. Compared with viral vectors, non-viral platforms offer improved safety profiles, greater design flexibility, lower production costs, and superior suitability for repeated administration. This review reports recent advancements in the development of non-viral platforms for CNS gene delivery and focuses on lipid-based nanoparticles, polymeric nanoparticles, exosome-based techniques, and new hybrid technologies. Particular emphasis is placed on nanoparticle modification approaches to enhance BBB penetration and enable delivery of genome-editing technologies (CRISPR\/Cas systems). The review provides explanations of clinical trials, regulatory considerations, and manufacturing issues that result from the recent developments noted above. It also explores the emerging role of artificial intelligence in supporting carrier design and enhancing delivery efficiency. Both artificial intelligence and non-viral platforms have the potential to facilitate the advancement of safe, effective, and repeatably administered gene therapies for patients with CNS disorders.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>Nanoparticles, lipid-based carriers, and exosomes are examples of nonviral gene-delivery methods for CNS diseases. These systems are superior to viral vectors in several respects, including greater BBB penetration, reduced propensity to elicit immune responses, and the ability to enable gene modification (e.g., CRISPR-Cas9). This graphical summary illustrates the platforms, methods for crossing the BBB, and their advantages over the use of viral vectors.<\/jats:p>","DOI":"10.1007\/s10571-026-01703-z","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T18:46:00Z","timestamp":1774118760000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Recent Advances in the Non-viral Delivery of Genes to Central Nervous System Disorders"],"prefix":"10.1007","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0069-4212","authenticated-orcid":false,"given":"Hany E.","family":"Marei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,21]]},"reference":[{"key":"1703_CR1","doi-asserted-by":"publisher","first-page":"571","DOI":"10.3390\/ph16040571","volume":"16","author":"M Abdelsalam","year":"2023","unstructured":"Abdelsalam M, Ahmed M, Osaid Z, Hamoudi R, Harati R (2023a) Insights into exosome transport through the blood\u2013brain barrier and the potential therapeutical applications in brain diseases. 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