{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:18:41Z","timestamp":1787933921879,"version":"build-2784847793"},"reference-count":38,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/100017347","name":"Nitto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017347","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\n                    Lipid nanoparticles (LNPs) are clinically validated carriers for the delivery of small interfering RNA (siRNA). Their efficient tissue accessibility and cellular uptake complement conjugated siRNA approaches. While chemical modifications are critical for stabilizing siRNAs and enhancing their potency (particularly in conjugated formats), their contribution in LNP delivery is not fully understood. Here, we systematically evaluated advanced sequence-modification patterns in siRNAs targeting\n                    <jats:italic toggle=\"yes\">YAP1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">WWTR1<\/jats:italic>\n                    to define their impact on LNP-siRNAs. We found that siRNAs fully incorporating 2\u2032-\n                    <jats:italic toggle=\"yes\">O<\/jats:italic>\n                    -methyl (2\u2032-OMe), 2\u2032-fluoro nucleotides achieved superior knockdown efficacy\n                    <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                    compared with partially modified LNP-siRNAs typically used in clinical drugs. Further increasing the proportion of 2\u2032-OMe to 86% did not impair RNA interference activity, and DNA substitutions provide additional opportunities for structural optimization to collectively enhance knockdown efficacy in mouse liver. In contrast, 5\u2032-(\n                    <jats:italic toggle=\"yes\">E<\/jats:italic>\n                    )-vinylphosphonate modification of the guide strand provides no benefit to knockdown efficacy\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">in\u00a0vivo<\/jats:italic>\n                    , likely owing to differences in endosomal trafficking between LNP and conjugated siRNAs. These findings provide a framework for chemical optimization of LNP-based siRNAs. The generation of siRNAs with greater efficacy and longer durability facilitates lower doses with less frequent administration, which mitigates LNP-associated toxicity and improves the therapeutic potential of LNP delivery systems.\n                  <\/jats:p>","DOI":"10.1177\/21593337261469503","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:48:02Z","timestamp":1784702882000},"page":"253-263","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimized Chemical Modifications Enhance Lipid Nanoparticle-Mediated siRNA Silencing of\n                    <i>YAP1<\/i>\n                    and\n                    <i>WWTR1<\/i>"],"prefix":"10.1177","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2427-5332","authenticated-orcid":false,"given":"Kaito","family":"Ueda","sequence":"first","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."},{"name":"Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Sakyo-ku, Kyoto, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Sato","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumpei","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Hashiba","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonari","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and Development Department, Corporate Technology Sector, Nitto Denko Corporation, Ibaraki, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Nucleic Acid Medicine Business Division, Drug Delivery Research and 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