{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1361694366455805952.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1016/j.actbio.2019.11.022"}},{"identifier":{"@type":"URI","@value":"https://api.elsevier.com/content/article/PII:S1742706119307639?httpAccept=text/xml"}},{"identifier":{"@type":"URI","@value":"https://api.elsevier.com/content/article/PII:S1742706119307639?httpAccept=text/plain"}},{"identifier":{"@type":"PMID","@value":"31733331"}},{"identifier":{"@type":"HANDLE","@value":"2115/76926"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles"}],"description":[{"notation":[{"@value":"Despite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, their poor stability and intracellular trafficking significantly hinders their use as potent small-sized LNPs. It has been reported that both the diffusion of lipid components from LNPs and the adsorption of proteins on the surface of LNPs are responsible for their decreased potency. To overcome this issue, we focused on the chemical structure of hydrophobic scaffolds of pH-sensitive cationic lipids with various lengths and shapes. LNPs composed of a pH-sensitive cationic lipid with long, linear scaffolds induced gene silencing in a dose-dependent manner, while LNPs with a classical scaffold length (C18) failed. Replacing the helper lipid from cholesterol to egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of ~22 nm and enhanced gene silencing activity. Most of the ESMs were located in the outer layer and functioned to stabilize the LNPs. Long, linear scaffolds contributed to immiscibility with phosphocholine-containing lipids including ESM. This contribution was dependent on the scaffold length of pH-sensitive cationic lipids. Although phosphocholine-containing lipids usually inhibit membrane fusion-mediated endosomal escape, long, linear scaffolds contributed to avoiding the inhibitory effect and to enhance the potency of the LNPs. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and the selection of appropriate helper lipids and will facilitate the development of highly potent small-sized LNPs. STATEMENT OF SIGNIFICANCE: Despite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, the size reduction-associated decrease in the stability and intracellular trafficking significantly hinders the development of potent small-sized LNPs. Our limited understanding of the mechanism underlying the reduced potency has also hindered the development of more potent small-sized LNPs. The findings of the present study indicate that long and linear hydrophobic scaffolds of pH-sensitive cationic lipids could overcome the loss of efficiency for nucleic acid delivery. In addition, the long hydrophobic scaffolds led to immiscibility with neutral phospholipids, resulting in efficient endosomal escape. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and will facilitate the development of highly potent small-sized LNPs."}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1420845751136651648","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"10735624"},{"@type":"NRID","@value":"1000010735624"},{"@type":"NRID","@value":"9000334746001"},{"@type":"NRID","@value":"9000020096217"},{"@type":"NRID","@value":"9000345197495"},{"@type":"NRID","@value":"9000391550745"},{"@type":"NRID","@value":"9000360551133"},{"@type":"NRID","@value":"9000267763092"},{"@type":"NRID","@value":"9000351082906"},{"@type":"NRID","@value":"9000288821713"},{"@type":"NRID","@value":"9000356630528"},{"@type":"NRID","@value":"9000340953481"},{"@type":"NRID","@value":"9000271444981"},{"@type":"NRID","@value":"9000398292716"},{"@type":"NRID","@value":"9000347642928"},{"@type":"NRID","@value":"9000380122874"},{"@type":"NRID","@value":"9000347136975"},{"@type":"NRID","@value":"9000006349387"},{"@type":"NRID","@value":"9000329896060"},{"@type":"NRID","@value":"9000271444954"},{"@type":"NRID","@value":"9000387366236"},{"@type":"NRID","@value":"9000019216967"},{"@type":"NRID","@value":"9000020507981"},{"@type":"NRID","@value":"9000242576831"},{"@type":"NRID","@value":"9000399756457"},{"@type":"NRID","@value":"9000237783767"},{"@type":"NRID","@value":"9000298901029"},{"@type":"NRID","@value":"9000346963391"},{"@type":"NRID","@value":"9000402080423"},{"@type":"NRID","@value":"9000336050013"},{"@type":"NRID","@value":"9000380476770"},{"@type":"NRID","@value":"9000347094432"},{"@type":"NRID","@value":"9000404130402"},{"@type":"NRID","@value":"9000410758058"},{"@type":"NRID","@value":"9000267763165"},{"@type":"NRID","@value":"9000267763215"},{"@type":"NRID","@value":"9000402285817"},{"@type":"NRID","@value":"9000347094425"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/y.sato"}],"foaf:name":[{"@value":"Yusuke 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Harashima"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"17427061"}],"prism:publicationName":[{"@value":"Acta Biomaterialia"}],"dc:publisher":[{"@value":"Elsevier BV"}],"prism:publicationDate":"2020-01","prism:volume":"102","prism:startingPage":"341","prism:endingPage":"350"},"reviewed":"false","dc:rights":["https://www.elsevier.com/tdm/userlicense/1.0/","https://www.elsevier.com/legal/tdmrep-license","http://creativecommons.org/licenses/by-nc-nd/4.0/"],"url":[{"@id":"https://api.elsevier.com/content/article/PII:S1742706119307639?httpAccept=text/xml"},{"@id":"https://api.elsevier.com/content/article/PII:S1742706119307639?httpAccept=text/plain"}],"createdAt":"2019-11-13","modifiedAt":"2025-10-28","foaf:topic":[{"@id":"https://cir.nii.ac.jp/all?q=pH-sensitive%20cationic%20lipid","dc:title":"pH-sensitive cationic lipid"},{"@id":"https://cir.nii.ac.jp/all?q=siRNA%20delivery","dc:title":"siRNA delivery"},{"@id":"https://cir.nii.ac.jp/all?q=460","dc:title":"460"},{"@id":"https://cir.nii.ac.jp/all?q=Drug%20Carriers","dc:title":"Drug Carriers"},{"@id":"https://cir.nii.ac.jp/all?q=Molecular%20Structure","dc:title":"Molecular Structure"},{"@id":"https://cir.nii.ac.jp/all?q=Microfluidic%20device","dc:title":"Microfluidic device"},{"@id":"https://cir.nii.ac.jp/all?q=Miscibility","dc:title":"Miscibility"},{"@id":"https://cir.nii.ac.jp/all?q=500","dc:title":"500"},{"@id":"https://cir.nii.ac.jp/all?q=Small-sized","dc:title":"Small-sized"},{"@id":"https://cir.nii.ac.jp/all?q=Hydrogen-Ion%20Concentration","dc:title":"Hydrogen-Ion Concentration"},{"@id":"https://cir.nii.ac.jp/all?q=Lipids","dc:title":"Lipids"},{"@id":"https://cir.nii.ac.jp/all?q=Luciferases,%20Firefly","dc:title":"Luciferases, Firefly"},{"@id":"https://cir.nii.ac.jp/all?q=Lipid%20nanoparticles","dc:title":"Lipid nanoparticles"},{"@id":"https://cir.nii.ac.jp/all?q=Humans","dc:title":"Humans"},{"@id":"https://cir.nii.ac.jp/all?q=Nanoparticles","dc:title":"Nanoparticles"},{"@id":"https://cir.nii.ac.jp/all?q=Gene%20Silencing","dc:title":"Gene Silencing"},{"@id":"https://cir.nii.ac.jp/all?q=RNA,%20Small%20Interfering","dc:title":"RNA, Small Interfering"},{"@id":"https://cir.nii.ac.jp/all?q=Hydrophobic%20scaffold","dc:title":"Hydrophobic scaffold"},{"@id":"https://cir.nii.ac.jp/all?q=Hydrophobic%20and%20Hydrophilic%20Interactions","dc:title":"Hydrophobic and Hydrophilic Interactions"},{"@id":"https://cir.nii.ac.jp/all?q=HeLa%20Cells","dc:title":"HeLa Cells"}],"project":[{"@id":"https://cir.nii.ac.jp/crid/1040000781958440064","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"17H05052"},{"@type":"JGN","@value":"JP17H05052"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17H05052/"}],"notation":[{"@language":"ja","@value":"In vivoゲノム編集による肝疾患治療の実現を目指した脂質ナノ粒子の創生"},{"@language":"en","@value":"Development of lipid nanoparicles for treatment of hepatic diseases by in vivo genome editing"}]},{"@id":"https://cir.nii.ac.jp/crid/1040000782006408576","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"18K19889"},{"@type":"JGN","@value":"JP18K19889"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18K19889/"}],"notation":[{"@language":"ja","@value":"組織浸透力に優れたsiRNA搭載極小脂質ナノ粒子による新規がん治療"},{"@language":"en","@value":"novel cancer treatment by highly permeable small-sized siRNA-loaded lipid nanoparticles"}]},{"@id":"https://cir.nii.ac.jp/crid/1040000782013677568","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"19H01170"},{"@type":"JGN","@value":"JP19H01170"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19H01170/"}],"notation":[{"@language":"ja","@value":"律速段階の解明に基づいたウイルスを凌駕する革新的医薬分子送達システムの創製"},{"@language":"en","@value":"Innovative gene/nucleic acid delivery system based on optimized intracellular trafficking steps"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1050025031473513984","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@language":"en","@value":"On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device"}]},{"@id":"https://cir.nii.ac.jp/crid/1050306506457361408","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@language":"en","@value":"A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo"},{"@value":"A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity <italic>in vitro</italic> and <italic>in vivo</italic>"},{"@value":"cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in 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