{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:15:28Z","timestamp":1785402928303,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,19]]},"group-title":"Bioengineering","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01 AG092015"],"award-info":[{"award-number":["R01 AG092015"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RF1 NS130334"],"award-info":[{"award-number":["RF1 NS130334"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Aging is the primary risk factor for chronic neurodegenerative diseases and is associated with alterations to cerebrospinal fluid (CSF) flow and clearance. CSF delivery is currently the most clinically advanced route of administration for oligonucleotide therapeutics, but it remains poorly understood how aging, which is rarely incorporated into clinical trials, impacts biodistribution, gene silencing activity, and potential toxicity of these compounds. Here, we evaluated a lipid-siRNA conjugate (L2-siRNA) for potential age-related changes to CSF-mediated delivery, mRNA silencing, and safety. We found that L2-siRNA exhibited comparable biodistribution and on-target silencing of Huntingtin (\n                  <jats:italic>Htt<\/jats:italic>\n                  ) between young and aged mice in all tested regions of the central nervous system (CNS) and across extended time points. Examining transport along CSF efflux routes revealed uptake in deep cervical lymph nodes and dura. Further, L2-siRNA did not generate detectable toxicity in the CNS or periphery of aged mice. A subset of studies benchmarked L2-siRNA against a C16 lipid-siRNA conjugate that recently entered clinical trials. Collectively, these results provide valuable insight into siRNA conjugate biodistribution and activity in the CNS in the context of aging and further establish the performance of L2-siRNA under conditions relevant to the treatment of neurodegenerative diseases.\n                <\/jats:p>","DOI":"10.64898\/2025.12.17.693452","type":"posted-content","created":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T04:50:38Z","timestamp":1766206238000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluating the effects of aging on biodistribution and gene silencing activity of lipid-siRNA conjugates delivered into cerebrospinal fluid"],"prefix":"10.64898","author":[{"given":"Alexander P.","family":"Ligocki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Sorets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M.","family":"Abdulrahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Francini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju Ha","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Ford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Lyons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Fritsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary E.","family":"Lamantia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Plamen P.","family":"Christov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig L.","family":"Duvall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan 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