Shielding of Lipid Nanoparticles for siRNA Delivery: Impact on Physicochemical Properties, Cytokine Induction, and Efficacy.
Shielding of Lipid Nanoparticles for siRNA Delivery: Impact on Physicochemical Properties, Cytokine Induction, and Efficacy.
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DOI：
10.1038/mtna.2014.61
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发表时间：
2014-11-18
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--
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将短干扰RNA（siRNA）配制成多组分脂质纳米粒（LNP）是用于肝脏递送和治疗性基因沉默的有效策略。本研究系统评价了聚乙二醇（PEG）密度对LNP理化性质、先天免疫应答刺激和体内疗效的影响。增加的PEG密度不仅屏蔽了LNP表面电荷，还降低了溶血活性，表明形成了空间屏障。此外，增加PEG密度降低了LNP的免疫刺激潜力，这反映在体内和体外的细胞因子诱导中。较高的PEG密度也阻碍了体内疗效，推测是由于与载脂蛋白E（ApoE）的结合减少，ApoE是一种用作肝细胞内源性靶向配体的蛋白质。这种效应可以通过将外源靶向配体掺入高度屏蔽的LNP中来克服，从而避免ApoE缔合的要求。因此，这些研究为合理设计具有最佳安全性和有效性的基于LNP的siRNA递送系统提供了有用的信息。
Formulation of short interfering RNA (siRNA) into multicomponent lipid nanoparticles (LNP) is an effective strategy for hepatic delivery and therapeutic gene silencing. This study systematically evaluated the effect of polyethylene glycol (PEG) density on LNP physicochemical properties, innate immune response stimulation, and in vivo efficacy. Increased PEG density not only shielded LNP surface charge but also reduced hemolytic activity, suggesting the formation of a steric barrier. In addition, increasing the PEG density reduced LNP immunostimulatory potential as reflected in cytokine induction both in vivo and in vitro. Higher PEG density also hindered in vivo efficacy, presumably due to reduced association with apolipoprotein E (ApoE), a protein which serves as an endogenous targeting ligand to hepatocytes. This effect could be overcome by incorporating an exogenous targeting ligand into the highly shielded LNPs, thereby circumventing the requirement for ApoE association. Therefore, these studies provide useful information for the rational design of LNP-based siRNA delivery systems with an optimal safety and efficacy profile.
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影响因子：
3.9
作者：
Bradley, AJ;Devine, DV;Brooks, DE
通讯作者：
Brooks, DE
影响因子：
10.8
作者：
Murthy, N;Robichaud, JR;Hoffman, AS
通讯作者：
Hoffman, AS
影响因子：
6.1
作者：
LEROUX, JC;DEJAEGHERE, F;GURNY, R
通讯作者：
GURNY, R
DOI：
10.1073/pnas.152463399
发表时间：
2002-10-01
影响因子：
11.1
作者：
Åkerman, ME;Chan, WCW;Ruoslahti, E
通讯作者：
Ruoslahti, E
影响因子：
12.4
作者：
Abrams, Marc T.;Koser, Martin L.;Sepp-Lorenzino, Laura
通讯作者：
Sepp-Lorenzino, Laura