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Red blood cell\u2010derived extracellular vesicles (RBCEVs) have the potential to address these challenges due to their non\u2010immunogenicity, non\u2010cytotoxicity, ability to be redosed, and suitability for nucleic acid loading. In this study, we demonstrate the efficacy and safety of RBCEV\u2010mediated nucleic acid delivery to the CNS. We found that RBCEVs administered through intrathecal injection are widely distributed across the CNS and efficiently taken up by neuronal cells. Delivery of RBCEVs loaded with GFP\u2010encoding plasmids results in GFP expression in neurons. Our data also highlight the potential of RBCEVs to deliver plasmids encoding secretory proteins, resulting in protein secretion within the cerebrospinal fluid. Furthermore, experiments conducted in both mouse and non\u2010human primate models indicate that intrathecal injection of plasmid\u2010loaded RBCEVs do not lead to any systemic or local acute toxicity. In summary, our findings illustrate the potential of the RBCEV\u2010based platform as a viable and safe approach for nucleic acid delivery to the CNS, facilitating further development of gene therapy for neurological disorders.<\/jats:p>","DOI":"10.1002\/jev2.70116","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T03:35:42Z","timestamp":1751859342000},"source":"Crossref","is-referenced-by-count":19,"title":["Extracellular Vesicles Administered via Intrathecal Injection Mediate Safe Delivery of Nucleic Acids to the Central Nervous System for Gene Therapy"],"prefix":"10.1002","volume":"14","author":[{"given":"Brenda Wan Shing","family":"Lam","sequence":"first","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Carmine Therapeutics Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thach Tuan","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan Thi Ngoc","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan Ngoc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore Singapore"},{"name":"Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harwin","family":"Sidik","sequence":"additional","affiliation":[{"name":"Carmine Therapeutics Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias B. 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