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To address these critical challenges, we developed an advanced actively targeted drug delivery system (DDS) utilizing a novel regioisomer of a folic acid-conjugated\n                    <jats:sc>l<\/jats:sc>\n                    -2,4-diaminobutyric acid octamer (FA-Dab8\u03b1) complexed with strategically chemically modified siRNA targeting the oncogenic small nucleolar RNA\n                    <jats:italic>SNORA22<\/jats:italic>\n                    . Although\n                    <jats:italic>SNORA22<\/jats:italic>\n                    represents a potent therapeutic target for suppressing PDAC invasion and metastasis, achieving robust in vivo efficacy requires highly optimized delivery vehicles. In this study, we systematically evaluated the structural impacts of ligand conjugation, demonstrating that the \u03b1-regioisomer (FA-Dab8\u03b1) spontaneously optimizes polyplex packing to achieve remarkably superior cellular uptake, lysosomal trafficking, and target gene knockdown over its \u03b3-counterpart. Furthermore, the strategic incorporation of phosphorothioate linkages and 2\u2032-\n                    <jats:italic>O<\/jats:italic>\n                    -methyl modifications conferred exceptional RNase resistance, maintaining payload stability within the bloodstream. The therapeutic potential of this optimized platform was evaluated in a clinically relevant preclinical mouse model established with human PDAC cell line-derived organoids. Systemic administration of the\n                    <jats:italic>SNORA22<\/jats:italic>\n                    siRNA\u2013FA\u2013Dab8\u03b1 complex resulted in profound tumor accumulation within 24\u00a0h and induced unprecedented tumor growth inhibition that significantly outperformed the clinical standard chemotherapy, gemcitabine plus paclitaxel (GP). Histopathological analysis revealed marked tumor necrosis and a drastic reduction in surrounding tissue infiltration, with zero detectable systemic toxicity in vital organs. These findings demonstrate that the precise structural optimization of ligand-modified oligopeptide carriers enables highly efficient oligonucleotide delivery, establishing the\n                    <jats:italic>SNORA22<\/jats:italic>\n                    siRNA\u2013FA-Dab8\u03b1 complex as a powerful and highly promising clinical strategy for refractory pancreatic cancer.\n                  <\/jats:p>","DOI":"10.1007\/s13577-026-01458-1","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:45:22Z","timestamp":1790790322000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of pancreatic cancer growth by an siRNA targeting SNORA22 and a folic acid-conjugated cationic oligopeptide"],"prefix":"10.1007","volume":"39","author":[{"given":"Kazuhiro","family":"Hiyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Nishigawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Takagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rintaro Iwata","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Furihata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazushige","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9165-7494","authenticated-orcid":false,"given":"Keisuke","family":"Taniuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"11","key":"1458_CR1","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1056\/NEJMra1404198","volume":"371","author":"DP Ryan","year":"2014","unstructured":"Ryan DP, Hong TS, Bardeesy N. 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