{"title":"脂质尾部长度对 mRNA 脂质纳米颗粒器官选择性的影响","authors":"Kazuki Hashiba, Masamitsu Taguchi, Sachiko Sakamoto, Ayaka Otsu, Yoshiki Maeda, Yuichi Suzuki, Hirofumi Ebe, Arimichi Okazaki, Hideyoshi Harashima, Yusuke Sato","doi":"10.1021/acs.nanolett.4c02566","DOIUrl":null,"url":null,"abstract":"<p><p>The delivery of mRNA molecules to organs beyond the liver is valuable for therapeutic applications. Functionalized lipid nanoparticles (LNPs) using exogenous mechanisms can regulate <i>in vivo</i> mRNA expression profiles from hepatocytes to extrahepatic tissues but lead to process complexity and cost escalation. Here, we report that mRNA expression gradually shifts from the liver to the spleen in an ionizable lipid tail length-dependent manner. Remarkably, this simple chemical strategy held true even when different ionizable lipid head structures were employed. As a potential mechanism underlying this discovery, our data suggest that 1,2-distearoyl-<i>sn</i>-glycero-3-phosphocholine (DSPC) is enriched on the surface of mRNA/LNPs with short-tail lipids. This feature limits their interaction with biological components, avoiding their rapid hepatic clearance. We also show that spleen-targeting LNPs loaded with SARS-CoV-2 receptor-binding domain (RBD) mRNA can efficiently induce immune responses and neutralize activity following intramuscular vaccination priming and boosting.</p>","PeriodicalId":53,"journal":{"name":"Nano Letters","volume":null,"pages":null},"PeriodicalIF":9.6000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Impact of Lipid Tail Length on the Organ Selectivity of mRNA-Lipid Nanoparticles.\",\"authors\":\"Kazuki Hashiba, Masamitsu Taguchi, Sachiko Sakamoto, Ayaka Otsu, Yoshiki Maeda, Yuichi Suzuki, Hirofumi Ebe, Arimichi Okazaki, Hideyoshi Harashima, Yusuke Sato\",\"doi\":\"10.1021/acs.nanolett.4c02566\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The delivery of mRNA molecules to organs beyond the liver is valuable for therapeutic applications. Functionalized lipid nanoparticles (LNPs) using exogenous mechanisms can regulate <i>in vivo</i> mRNA expression profiles from hepatocytes to extrahepatic tissues but lead to process complexity and cost escalation. Here, we report that mRNA expression gradually shifts from the liver to the spleen in an ionizable lipid tail length-dependent manner. Remarkably, this simple chemical strategy held true even when different ionizable lipid head structures were employed. As a potential mechanism underlying this discovery, our data suggest that 1,2-distearoyl-<i>sn</i>-glycero-3-phosphocholine (DSPC) is enriched on the surface of mRNA/LNPs with short-tail lipids. This feature limits their interaction with biological components, avoiding their rapid hepatic clearance. We also show that spleen-targeting LNPs loaded with SARS-CoV-2 receptor-binding domain (RBD) mRNA can efficiently induce immune responses and neutralize activity following intramuscular vaccination priming and boosting.</p>\",\"PeriodicalId\":53,\"journal\":{\"name\":\"Nano Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.6000,\"publicationDate\":\"2024-10-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nano Letters\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.nanolett.4c02566\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nano Letters","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1021/acs.nanolett.4c02566","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Impact of Lipid Tail Length on the Organ Selectivity of mRNA-Lipid Nanoparticles.
The delivery of mRNA molecules to organs beyond the liver is valuable for therapeutic applications. Functionalized lipid nanoparticles (LNPs) using exogenous mechanisms can regulate in vivo mRNA expression profiles from hepatocytes to extrahepatic tissues but lead to process complexity and cost escalation. Here, we report that mRNA expression gradually shifts from the liver to the spleen in an ionizable lipid tail length-dependent manner. Remarkably, this simple chemical strategy held true even when different ionizable lipid head structures were employed. As a potential mechanism underlying this discovery, our data suggest that 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) is enriched on the surface of mRNA/LNPs with short-tail lipids. This feature limits their interaction with biological components, avoiding their rapid hepatic clearance. We also show that spleen-targeting LNPs loaded with SARS-CoV-2 receptor-binding domain (RBD) mRNA can efficiently induce immune responses and neutralize activity following intramuscular vaccination priming and boosting.
期刊介绍:
Nano Letters serves as a dynamic platform for promptly disseminating original results in fundamental, applied, and emerging research across all facets of nanoscience and nanotechnology. A pivotal criterion for inclusion within Nano Letters is the convergence of at least two different areas or disciplines, ensuring a rich interdisciplinary scope. The journal is dedicated to fostering exploration in diverse areas, including:
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