Lipid nanoparticle-mediated mRNA delivery to CD34+ cells in rhesus monkeys

IF 33.1 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Nature biotechnology Pub Date : 2024-11-22 DOI:10.1038/s41587-024-02470-2

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

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引用次数: 0

Abstract

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.

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脂质纳米颗粒介导的 mRNA 在恒河猴 CD34+ 细胞中的传递

体内外工程造血干细胞（HSCs）移植可产生强有力的临床反应，但也存在因骨髓动员、化疗调理和其他因素引起不良事件的风险。体内造血干细胞的改造使用了装饰有靶向分子的脂质纳米颗粒（LNPs），这增加了制造的复杂性。在此，我们筛选了 105 种不含靶向配体的 LNPs，以确保它们能在小鼠骨髓中有效归巢。我们报告了一种名为 LNP67 的 LNP，它能以 0.25 和 0.4 mg kg-1 的剂量向体内小鼠造血干细胞、体外原代人类造血干细胞和体内恒河猴（Macaca mulatta）CD34+细胞输送 mRNA。无需动员和调节，LNP67 就能介导 mRNA 向恒河猴的造血干细胞及其祖细胞（HSPCs）以及肝脏递送，而无需激活血清细胞因子。这些数据支持了一种假设，即在体内向非人灵长类动物的造血干细胞和造血祖细胞输送 mRNA 是可行的，无需靶向配体。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature biotechnology 工程技术-生物工程与应用微生物

CiteScore

63.00

自引率

1.70%

发文量

382

审稿时长

3 months

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