Hyejin Kim, Ryan Zenhausern, Kara Gentry, Liming Lian, Sebastian G. Huayamares, Afsane Radmand, David Loughrey, Ananda R. Podilapu, Marine Z. C. Hatit, Huanzhen Ni, Andrea Li, Aram Shajii, Hannah E. Peck, Keyi Han, Xuanwen Hua, Shu Jia, Michele Martinez, Charles Lee, Philip J. Santangelo, Alice Tarantal, James E. Dahlman
{"title":"脂质纳米颗粒介导的 mRNA 在恒河猴 CD34+ 细胞中的传递","authors":"Hyejin Kim, Ryan Zenhausern, Kara Gentry, Liming Lian, Sebastian G. Huayamares, Afsane Radmand, David Loughrey, Ananda R. Podilapu, Marine Z. C. Hatit, Huanzhen Ni, Andrea Li, Aram Shajii, Hannah E. Peck, Keyi Han, Xuanwen Hua, Shu Jia, Michele Martinez, Charles Lee, Philip J. Santangelo, Alice Tarantal, James E. Dahlman","doi":"10.1038/s41587-024-02470-2","DOIUrl":null,"url":null,"abstract":"<p>Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse. We report an LNP named LNP<sup>67</sup> that delivers mRNA to murine HSCs in vivo, primary human HSCs ex vivo and CD34<sup>+</sup> cells in rhesus monkeys (<i>Macaca mulatta</i>) in vivo at doses of 0.25 and 0.4 mg kg<sup>−1</sup>. Without mobilization and conditioning, LNP<sup>67</sup> can mediate delivery of mRNA to HSCs and their progenitor cells (HSPCs), as well as to the liver in rhesus monkeys, without serum cytokine activation. These data support the hypothesis that in vivo delivery to HSCs and HSPCs in nonhuman primates is feasible without targeting ligands.</p>","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"16 1","pages":""},"PeriodicalIF":33.1000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lipid nanoparticle-mediated mRNA delivery to CD34+ cells in rhesus monkeys\",\"authors\":\"Hyejin Kim, Ryan Zenhausern, Kara Gentry, Liming Lian, Sebastian G. Huayamares, Afsane Radmand, David Loughrey, Ananda R. Podilapu, Marine Z. C. Hatit, Huanzhen Ni, Andrea Li, Aram Shajii, Hannah E. Peck, Keyi Han, Xuanwen Hua, Shu Jia, Michele Martinez, Charles Lee, Philip J. Santangelo, Alice Tarantal, James E. Dahlman\",\"doi\":\"10.1038/s41587-024-02470-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse. We report an LNP named LNP<sup>67</sup> that delivers mRNA to murine HSCs in vivo, primary human HSCs ex vivo and CD34<sup>+</sup> cells in rhesus monkeys (<i>Macaca mulatta</i>) in vivo at doses of 0.25 and 0.4 mg kg<sup>−1</sup>. Without mobilization and conditioning, LNP<sup>67</sup> can mediate delivery of mRNA to HSCs and their progenitor cells (HSPCs), as well as to the liver in rhesus monkeys, without serum cytokine activation. These data support the hypothesis that in vivo delivery to HSCs and HSPCs in nonhuman primates is feasible without targeting ligands.</p>\",\"PeriodicalId\":19084,\"journal\":{\"name\":\"Nature biotechnology\",\"volume\":\"16 1\",\"pages\":\"\"},\"PeriodicalIF\":33.1000,\"publicationDate\":\"2024-11-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature biotechnology\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://doi.org/10.1038/s41587-024-02470-2\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature biotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1038/s41587-024-02470-2","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Lipid nanoparticle-mediated mRNA delivery to CD34+ cells in rhesus monkeys
Transplantation of ex vivo engineered hematopoietic stem cells (HSCs) can lead to robust clinical responses but carries risks of adverse events from bone marrow mobilization, chemotherapy conditioning and other factors. HSCs have been modified in vivo using lipid nanoparticles (LNPs) decorated with targeting moieties, which increases manufacturing complexity. Here we screen 105 LNPs without targeting ligands for effective homing to the bone marrow in mouse. We report an LNP named LNP67 that delivers mRNA to murine HSCs in vivo, primary human HSCs ex vivo and CD34+ cells in rhesus monkeys (Macaca mulatta) in vivo at doses of 0.25 and 0.4 mg kg−1. Without mobilization and conditioning, LNP67 can mediate delivery of mRNA to HSCs and their progenitor cells (HSPCs), as well as to the liver in rhesus monkeys, without serum cytokine activation. These data support the hypothesis that in vivo delivery to HSCs and HSPCs in nonhuman primates is feasible without targeting ligands.
期刊介绍：
Nature Biotechnology is a monthly journal that focuses on the science and business of biotechnology. It covers a wide range of topics including technology/methodology advancements in the biological, biomedical, agricultural, and environmental sciences. The journal also explores the commercial, political, ethical, legal, and societal aspects of this research.
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In summary, Nature Biotechnology is a comprehensive journal that covers both the scientific and business aspects of biotechnology. It strives to provide researchers with valuable research papers and news while also delivering important scientific advancements to the business community.
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