In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles,Nano Letters

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In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles
Nano Letters ( IF 9.6 ) Pub Date : 2023-03-29 , DOI: 10.1021/acs.nanolett.3c00304
Dennis Shi _{1,

2} , Sho Toyonaga _{2,

3} , Daniel G Anderson _{1,

2,

4,

5}

Affiliation

Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg^–1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.

中文翻译：

通过靶向脂质纳米颗粒将 RNA 体内递送至造血干细胞和祖细胞

离体自体造血干细胞 (HSC) 基因疗法为治疗血液病提供了新疗法。然而，由于制造复杂性和所需调理方案导致的毒性，这些疗法有几个局限性。在这里，我们开发了一种 c-kit (CD117) 抗体靶向脂质纳米颗粒 (LNP)，在单次静脉注射后，可以将 RNA（siRNA 和 mRNA）递送至啮齿动物体内的HSC。这种靶向递送系统不需要干细胞采集、培养或动员 HSC 来促进递送。^{我们还表明，以 1 mg kg –1}的剂量递送 Cre 重组酶 mRNA可以促进体内几乎所有 (∼90%) 造血干细胞和祖细胞 (HSPC) 的基因编辑，并且经过编辑的细胞保留了它们的干性和功能，可以生成高水平的经过编辑的成熟免疫细胞。

更新日期：2023-03-29

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