Lulu Xue, Gan Zhao, Ningqiang Gong, Xuexiang Han, Sarah J. Shepherd, Xinhong Xiong, Zebin Xiao, Rohan Palanki, Junchao Xu, Kelsey L. Swingle, Claude C. Warzecha, Rakan El-Mayta, Vivek Chowdhary, Il-Chul Yoon, Jingcheng Xu, Jiaxi Cui, Yi Shi, Mohamad-Gabriel Alameh, Karin Wang, Lili Wang, Darrin J. Pochan, Drew Weissman, Andrew E. Vaughan, James M. Wilson, Michael J. Mitchell
{"title":"硅氧烷包裹脂质纳米颗粒的组合设计可增强细胞内处理能力，实现组织特异性 mRNA 治疗递送","authors":"Lulu Xue, Gan Zhao, Ningqiang Gong, Xuexiang Han, Sarah J. Shepherd, Xinhong Xiong, Zebin Xiao, Rohan Palanki, Junchao Xu, Kelsey L. Swingle, Claude C. Warzecha, Rakan El-Mayta, Vivek Chowdhary, Il-Chul Yoon, Jingcheng Xu, Jiaxi Cui, Yi Shi, Mohamad-Gabriel Alameh, Karin Wang, Lili Wang, Darrin J. Pochan, Drew Weissman, Andrew E. Vaughan, James M. Wilson, Michael J. Mitchell","doi":"10.1038/s41565-024-01747-6","DOIUrl":null,"url":null,"abstract":"<p>Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si<sub>5</sub>-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.</p>","PeriodicalId":18915,"journal":{"name":"Nature nanotechnology","volume":null,"pages":null},"PeriodicalIF":38.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery\",\"authors\":\"Lulu Xue, Gan Zhao, Ningqiang Gong, Xuexiang Han, Sarah J. Shepherd, Xinhong Xiong, Zebin Xiao, Rohan Palanki, Junchao Xu, Kelsey L. Swingle, Claude C. Warzecha, Rakan El-Mayta, Vivek Chowdhary, Il-Chul Yoon, Jingcheng Xu, Jiaxi Cui, Yi Shi, Mohamad-Gabriel Alameh, Karin Wang, Lili Wang, Darrin J. Pochan, Drew Weissman, Andrew E. Vaughan, James M. Wilson, Michael J. Mitchell\",\"doi\":\"10.1038/s41565-024-01747-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si<sub>5</sub>-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.</p>\",\"PeriodicalId\":18915,\"journal\":{\"name\":\"Nature nanotechnology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":38.1000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature nanotechnology\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1038/s41565-024-01747-6\",\"RegionNum\":1,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature nanotechnology","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1038/s41565-024-01747-6","RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","Score":null,"Total":0}
Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery
Systemic delivery of messenger RNA (mRNA) for tissue-specific targeting using lipid nanoparticles (LNPs) holds great therapeutic potential. Nevertheless, how the structural characteristics of ionizable lipids (lipidoids) impact their capability to target cells and organs remains unclear. Here we engineered a class of siloxane-based ionizable lipids with varying structures and formulated siloxane-incorporated LNPs (SiLNPs) to control in vivo mRNA delivery to the liver, lung and spleen in mice. The siloxane moieties enhance cellular internalization of mRNA-LNPs and improve their endosomal escape capacity, augmenting their mRNA delivery efficacy. Using organ-specific SiLNPs to deliver gene editing machinery, we achieve robust gene knockout in the liver of wild-type mice and in the lungs of both transgenic GFP and Lewis lung carcinoma (LLC) tumour-bearing mice. Moreover, we showed effective recovery from viral infection-induced lung damage by delivering angiogenic factors with lung-targeted Si5-N14 LNPs. We envision that our SiLNPs will aid in the clinical translation of mRNA therapeutics for next-generation tissue-specific protein replacement therapies, regenerative medicine and gene editing.
期刊介绍：
Nature Nanotechnology is a prestigious journal that publishes high-quality papers in various areas of nanoscience and nanotechnology. The journal focuses on the design, characterization, and production of structures, devices, and systems that manipulate and control materials at atomic, molecular, and macromolecular scales. It encompasses both bottom-up and top-down approaches, as well as their combinations.
Furthermore, Nature Nanotechnology fosters the exchange of ideas among researchers from diverse disciplines such as chemistry, physics, material science, biomedical research, engineering, and more. It promotes collaboration at the forefront of this multidisciplinary field. The journal covers a wide range of topics, from fundamental research in physics, chemistry, and biology, including computational work and simulations, to the development of innovative devices and technologies for various industrial sectors such as information technology, medicine, manufacturing, high-performance materials, energy, and environmental technologies. It includes coverage of organic, inorganic, and hybrid materials.
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