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These materials can either encapsulate or be functionalized to bind nucleic acids and protect them from degradation. To effectively elicit changes to gene expression, the nanoparticle carrier needs to undergo a series of steps intracellularly, from interacting with the cellular membrane to facilitate cellular uptake to endosomal escape and nucleic acid release. Adjusting physiochemical properties of the nanoparticles, such as size, charge, and targeting ligands, can improve cellular uptake and ultimately gene delivery. Applications in the central nervous system (CNS; i.e., neurological diseases, brain cancers) face further extracellular barriers for a gene\u2010carrying nanoparticle to surpass, with the most significant being the blood\u2013brain barrier (BBB). Approaches to overcome these extracellular challenges to deliver nanoparticles into the CNS include systemic, intracerebroventricular, intrathecal, and intranasal administration. This review describes and compares different biomaterials for nonviral nanoparticle\u2010mediated gene therapy to the CNS and explores challenges and recent preclinical and clinical developments in overcoming barriers to nanoparticle\u2010mediated delivery to the brain.<\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Therapeutic Approaches and Drug Discovery &gt; Nanomedicine for Neurological Disease<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Therapeutic Approaches and Drug Discovery &gt; Emerging Technologies<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Nanotechnology Approaches to Biology &gt; Nanoscale Systems in Biology<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1002\/wnan.1853","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T02:15:19Z","timestamp":1664849719000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Nonviral nanoparticle gene delivery into the\n                    <scp>CNS<\/scp>\n                    for neurological disorders and brain cancer applications"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0455-0635","authenticated-orcid":false,"given":"Joanna","family":"Yang","sequence":"first","affiliation":[{"name":"Departments of Biomedical Engineering, Ophthalmology, Oncology, Neurosurgery, Materials Science &amp; Engineering, and Chemical &amp; Biomolecular Engineering Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-9155","authenticated-orcid":false,"given":"Kathryn M.","family":"Luly","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Engineering, Ophthalmology, Oncology, Neurosurgery, Materials Science &amp; Engineering, and Chemical &amp; Biomolecular Engineering Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4176-3808","authenticated-orcid":false,"given":"Jordan J.","family":"Green","sequence":"additional","affiliation":[{"name":"Departments of Biomedical Engineering, Ophthalmology, Oncology, Neurosurgery, Materials Science &amp; Engineering, and Chemical &amp; Biomolecular Engineering Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"e_1_2_14_1_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"e_1_2_14_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.03.025"},{"key":"e_1_2_14_1_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577"},{"key":"e_1_2_14_2_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2018.12.009"},{"key":"e_1_2_14_2_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c01592"},{"key":"e_1_2_14_2_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2015.05.043"},{"key":"e_1_2_14_2_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0177-5"},{"key":"e_1_2_14_2_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp800051m"},{"key":"e_1_2_14_2_7_1","doi-asserted-by":"publisher","DOI":"10.2147\/NSA.S99986"},{"key":"e_1_2_14_2_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327119846924"},{"key":"e_1_2_14_2_9_1","unstructured":"Alnylam Pharmaceuticals. 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