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However, an siRNA modality capable of simultaneously modulating gene pairs would be invaluable for treating complex neurodegenerative disorders, where more than one pathway contributes to pathogenesis. Currently, the parameters and scaffold considerations for multi-targeting nucleic acid modalities in the CNS are undefined. Here, we propose a framework for designing unimolecular \u2018dual-targeting\u2019 divalent siRNAs capable of co-silencing two genes in the CNS. We systematically adjusted the original CNS-active divalent siRNA and identified that connecting two sense strands 3\u2032 and 5\u2032 through an intra-strand linker enabled a functional dual-targeting scaffold, greatly simplifying the synthetic process. Our findings demonstrate that the dual-targeting siRNA supports at least two months of maximal distribution and target silencing in the mouse CNS. The dual-targeting divalent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g. Huntington's disease: MSH3 and HTT; Alzheimer's disease: APOE and JAK1) with similar potency to a mixture of single-targeting divalent siRNAs against each gene. This work enhances the potential for CNS modulation of disease-related gene pairs using a unimolecular siRNA.<\/jats:p>","DOI":"10.1093\/nar\/gkae368","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T15:30:06Z","timestamp":1713972606000},"page":"6099-6113","source":"Crossref","is-referenced-by-count":36,"title":["A programmable dual-targeting siRNA scaffold supports potent two-gene modulation in the central nervous system"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2577-2336","authenticated-orcid":false,"given":"Jillian","family":"Belgrad","sequence":"first","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8913-0519","authenticated-orcid":false,"given":"Qi","family":"Tang","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; 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Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0012-5623","authenticated-orcid":false,"given":"Dan","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Luu","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Bramato","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Allen","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; 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Worcester , MA , USA"},{"name":"Department of Medicine, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"DiFiglia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital ; Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6928-8071","authenticated-orcid":false,"given":"Anastasia","family":"Khvorova","sequence":"additional","affiliation":[{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School ; Worcester , MA , USA"},{"name":"Program in Molecular Medicine, University of Massachusetts Chan Medical School ; Worcester , MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,10]]},"reference":[{"key":"2024062400062901100_B1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nbt.3765","article-title":"The chemical evolution of oligonucleotide therapies of clinical utility","volume":"35","author":"Khvorova","year":"2017","journal-title":"Nat. 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