Kim Hyejin, Zenhausern Ryan, Gentry Kara, Lian Liming, Huayamares Sebastian G, Radmand Afsane, Loughrey David, Podilapu Ananda R, Hatit Marine Z C, Ni Huanzhen, Li Andrea, Shajii Aram, Peck Hannah E, Han Keyi, Hua Xuanwen, Jia Shu, Martinez Michele, Lee Charles, Santangelo Philip J, Tarantal Alice, Dahlman James E
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
Nat Biotechnol. 2024 Nov 22. doi: 10.1038/s41587-024-02470-2.
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 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. Without mobilization and conditioning, LNP 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.
体外工程化造血干细胞（HSCs）移植可带来显著的临床反应，但存在骨髓动员、化疗预处理及其他因素导致不良事件的风险。造血干细胞已在体内使用修饰有靶向部分的脂质纳米颗粒（LNPs）进行改造，这增加了制造复杂性。在此，我们筛选了105种无靶向配体的脂质纳米颗粒，以确定其在小鼠体内有效归巢至骨髓的能力。我们报告了一种名为LNP的脂质纳米颗粒，它能以0.25和0.4mg/kg的剂量，将mRNA分别递送至小鼠体内的造血干细胞、体外的原代人造血干细胞以及恒河猴（猕猴）体内的CD34细胞。在无动员和预处理的情况下，LNP可介导mRNA递送至造血干细胞及其祖细胞（HSPCs），以及恒河猴的肝脏，且无需血清细胞因子激活。这些数据支持了以下假设：在非人灵长类动物中，无需靶向配体即可实现对造血干细胞和造血干细胞祖细胞的体内递送。
