Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.
Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.
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通过吸入方式构建用于增强信使核糖核酸（mRNA）细胞内递送的脂质纳米颗粒
DOI：
10.1021/acsnano.2c05647
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发表时间：
2022-09-27
期刊：
影响因子：
17.1
通讯作者：
Sahay, Gaurav
中科院分区：
文献类型：
--
作者：
Kim, Jeonghwan;Jozic, Antony;Lin, Yuxin;Eygeris, Yulia;Bloom, Elissa;Tan, Xiaochen;Acosta, Christopher;MacDonald, Kelvin D.;Welsher, Kevin D.;Sahay, Gaurav
关键词：
尽管脂质纳米粒(LNP)成功地有效和安全地递送了信使核糖核酸疫苗，但基于吸入的信使核糖核酸治疗肺部疾病仍然具有挑战性。在雾化过程中，由于剪切力的作用，LNP容易崩解，导致不能有效地传递。因此，LNP需要在雾化和粘液渗透过程中保持稳定，但又不稳定，足以使内体逃逸。为了满足这些相反的需求，我们利用聚乙二醇脂类来增强脂多糖的表面稳定性，并加入胆固醇类似物β-谷甾醇来改善内体逃逸。聚乙二醇组分的增加提高了粘液穿透和剪切阻力，而β-谷甾醇则为其提供了多面体的形状，方便了内质粒的逃逸。优化后的LNP具有均匀的颗粒分布、多面体形态、快速的粘膜扩散和增强的基因转染性。吸入LNPs可导致小鼠肺内局部蛋白质的产生，而不会对肺或全身产生毒性。反复给药这些LNP导致了肺部持续的蛋白质生产。最后，将编码囊性纤维化跨膜电导调节因子(CFTR)的信使核糖核酸(MRNAs)雾化后输送到CFTR缺乏的动物模型中，导致该治疗性蛋白的肺表达。本研究证明了基于LNP的可吸入信使核糖核酸疗法临床翻译的合理设计方法。
Despite lipid nanoparticles’ (LNP) success in the effective and safe delivery of mRNA vaccines, an inhalation-based mRNA therapy for lung diseases remains challenging. LNP tend to disintegrate due to shear stress during aerosolization, leading to ineffective delivery. Therefore, LNP need to remain stable through the process of nebulization and mucus penetration, yet labile enough for endosomal escape. To meet these opposing needs, we utilized PEG lipid to enhance the surficial stability of LNP with the inclusion of cholesterol analogs, β-sitosterol, to improve endosomal escape. Increased PEG concentrations in LNP enhanced the shear resistance and mucus penetration, while β-sitosterol provided LNP with a polyhedral shape facilitating endosomal escape. The optimized LNP exhibited a uniform particle distribution, a polyhedral morphology, and a rapid mucosal diffusion with enhanced gene transfection. Inhaled LNPs led to localized protein production in the mouse lung without pulmonary or systemic toxicity. Repeated administration of these LNP led to sustained protein production in the lungs. Lastly, mRNA encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after nebulization to a CFTR deficient animal model, resulting in the pulmonary expression of this therapeutic protein. This study demonstrated the rational design approach for clinical translation of inhalable LNP-based mRNA therapies.
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影响因子：
6.6
作者：
Herrera M;Kim J;Eygeris Y;Jozic A;Sahay G
通讯作者：
Sahay G
DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
DOI：
10.1073/pnas.2109256118
发表时间：
2021-12-28
影响因子：
11.1
作者：
Dilliard, Sean A.;Cheng, Qiang;Siegwart, Daniel J.
通讯作者：
Siegwart, Daniel J.
影响因子：
7.3
作者：
Lu L;Li J;Moussaoui M;Boix E
通讯作者：
Boix E
DOI：
10.1038/mt.2012.7
发表时间：
2012-05
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
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作者：
通讯作者：
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