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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >PNAS Plus: Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles
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PNAS Plus: Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles

机译：PNAS Plus：通过功能化脂质纳米颗粒传递的mRNA成功重编程细胞蛋白质生产

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The development of safe and efficacious gene vectors has limited greatly the potential for therapeutic treatments based on messenger RNA (mRNA). Lipid nanoparticles (LNPs) formed by an ionizable cationic lipid (here DLin-MC3-DMA), helper lipids (distearoylphosphatidylcholine, DSPC, and cholesterol), and a poly(ethylene glycol) (PEG) lipid have been identified as very promising delivery vectors of short interfering RNA (siRNA) in different clinical phases; however, delivery of high-molecular weight RNA has been proven much more demanding. Herein we elucidate the structure of hEPO modified mRNA-containing LNPs of different sizes and show how structural differences affect transfection of human adipocytes and hepatocytes, two clinically relevant cell types. Employing small-angle scattering, we demonstrate that LNPs have a disordered inverse hexagonal internal structure with a characteristic distance around 6 nm in presence of mRNA, whereas LNPs containing no mRNA do not display this structure. Furthermore, using contrast variation small-angle neutron scattering, we show that one of the lipid components, DSPC, is localized mainly at the surface of mRNA-containing LNPs. By varying LNP size and surface composition we demonstrate that both size and structure have significant influence on intracellular protein production. As an example, in both human adipocytes and hepatocytes, protein expression levels for 130 nm LNPs can differ as much as 50-fold depending on their surface characteristics, likely due to a difference in the ability of LNP fusion with the early endosome membrane. We consider these discoveries to be fundamental and opening up new possibilities for rational design of synthetic nanoscopic vehicles for mRNA delivery.
机译：安全有效的基因载体的开发极大地限制了基于信使RNA（mRNA）的治疗方法的潜力。由可电离的阳离子脂质（此处为DLin-MC3-DMA），辅助脂质（二硬脂酰磷脂酰胆碱，DSPC和胆固醇）和聚（乙二醇）（PEG）脂质形成的脂质纳米颗粒（LNP）已被认为是非常有前途的递送载体不同临床阶段的短干扰RNA（siRNA）的检测；但是，高分子量RNA的交付已被证明要求更高。本文中，我们阐明了不同大小的hEPO修饰的含mRNA的LNP的结构，并显示了结构差异如何影响人类脂肪细胞和肝细胞这两种临床相关细胞类型的转染。利用小角度散射，我们证明LNP具有无序的六边形逆内部结构，在存在mRNA时特征距离约为6 nm，而不含mRNA的LNP则不显示此结构。此外，使用对比度变化小角中子散射，我们表明脂质成分之一，DSPC，主要位于包含mRNA的LNPs的表面。通过改变LNP的大小和表面组成，我们证明大小和结构都对细胞内蛋白质的产生具有重要影响。例如，在人类脂肪细胞和肝细胞中，取决于其表面特征，130 nm LNP的蛋白质表达水平可能相差多达50倍，这可能是由于LNP与早期内体膜融合的能力不同所致。我们认为这些发现是基础，为合理设计合成的纳米载体用于mRNA传递开辟了新的可能性。

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