{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:06:44Z","timestamp":1779782804493,"version":"3.53.1"},"reference-count":102,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["EMDR\/SG\/11\/2023\u20105582"],"award-info":[{"award-number":["EMDR\/SG\/11\/2023\u20105582"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The CRISPR\u2010Cas9 genome\u2010editing technique offers a promising therapeutic strategy for genetic disorders, including neurodegenerative diseases like Alzheimer's disease (AD), characterised by inherited susceptibility and progressive cognitive decline, as well as other hallmarks such as amyloid beta (A\u03b2\n                    <jats:sub>1\u201342<\/jats:sub>\n                    ) plaques and neurofibril tangles (NFTs). However, the blood\u2013brain barrier (BBB) poses a significant challenge to the effectiveness of gene editing components in the affected brain region and impedes clinical translation. This comprehensive review compares various CRISPR\u2010Cas9 delivery vectors, viral, nonviral and physical, with a focus on their efficacy in neurological diseases such as AD. Viral vectors viz., adeno\u2010associated viruses (AAVs) and lentiviruses (LVs) demonstrate high transduction efficiency and BBB permeability. AAVs are preferred for their low immunogenicity, minimal toxicity, high neuronal tropism and episomal persistence, enabling sustained expression without insertional mutagenesis. LVs offer larger genetic payloads but raise concerns about genomic integration and potential oncogenesis, though integration\u2010defective variants mitigate these risks. Nonviral vectors, including peptide and polymer\u2010based nanoparticles, lipid nanoparticles (LNPs) and Inorganic carriers such as gold and silver nanoparticles, are less immunogenic and easier to handle but require further optimisation for in\u00a0vivo BBB crossing and endosomal escape. Physical methods such as electroporation and microinjection are suitable for in\u00a0vitro\/ex vivo use, while novel CNS\u2010targeted strategies, such as RVG\u2010tagged particles, TfR\u2010directed LNPs and engineered AAV variants, enhance brain penetration via receptor\u2010mediated transcytosis. These preclinical studies show that these technologies can successfully edit genes and provide therapeutic benefits, including amyloid reduction and cognitive improvement in AD models. Yet off\u2010target effects, immune responses and regulatory hurdles persist. Overall, continuous innovation in delivery vector design and safety profile\u2010targeting strategies is crucial for advancing CRISPR\u2010Cas9 towards clinical therapies for AD\u2010based therapies and related neurological disorders.\n                  <\/jats:p>","DOI":"10.1002\/jgm.70095","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T03:16:21Z","timestamp":1778469381000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rational Design and Optimisation of CRISPR\u2010Cas9 Delivery Systems for Targeted Genomic Transformation"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1086-4316","authenticated-orcid":false,"given":"Kalpana","family":"Pandya","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, School of Pharmacy &amp; Technology Management SVKM's NMIMS University, Mukesh Patel Technology Park  Mumbai 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