Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery
Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery
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DOI：
10.1021/acs.nanolett.0c01386
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发表时间：
2020-06-10
期刊：
影响因子：
10.8
通讯作者：
Sahay, Gaurav
中科院分区：
文献类型：
--
作者：
Eygeris, Yulia;Patel, Siddharth;Sahay, Gaurav
脂质纳米颗粒（LNP）包装的mRNA疫苗已用于对抗感染性疾病，如COVID-19，但其结构特征仍不清楚。胆固醇是LNP内的主要成分，有助于影响基因递送的其形态。在这里，我们研究的结构LNP含有胆固醇衍生物，使用电子显微镜，差示扫描量热法，膜流动性测定。用胆固醇的C24烷基衍生物配制的LNP显示多晶型形状和不同程度的多层性和脂质分配，可能是由于相分离。向胆固醇主链的C24烷基尾部添加甲基和乙基诱导多层性（与胆固醇相比增加>50%），而添加双键诱导脂质分配（与胆固醇相比增加>90%）。具有多层和多面结构以及层状脂质相的LNP显示出较高的基因转染。解开mRNA-LNP的结构可以使它们的合理设计朝向增强的基因递送。
Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure of LNPs containing cholesterol derivatives using electron microscopy, differential scanning calorimetry, and membrane fluidity assays. LNPs formulated with C24 alkyl derivatives of cholesterol show a polymorphic shape and various degrees of multilamellarity and lipid partitioning, likely due to phase separation. The addition of methyl and ethyl groups to the C24 alkyl tail of the cholesterol backbone induces multilamellarity (>50% increase compared to cholesterol), while the addition of a double bond induces lipid partitioning (>90% increase compared to cholesterol). LNPs with multilamellar and faceted structures, as well as a lamellar lipid phase, showed higher gene transfection. Unraveling the structure of mRNA-LNPs can enable their rational design toward enhanced gene delivery.