Chemistry of Lipid Nanoparticles for RNA Delivery.
Chemistry of Lipid Nanoparticles for RNA Delivery.
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DOI：
10.1021/acs.accounts.1c00544
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发表时间：
2022-01-04
影响因子：
18.3
通讯作者：
Sahay, Gaurav
中科院分区：
文献类型：
--
作者：
Eygeris, Yulia;Gupta, Mohit;Sahay, Gaurav
脂质纳米粒（LNP）是一种具有均匀脂质核心的脂质囊泡。这些囊泡广泛用于小分子药物和核酸递送，并且由于其作为COVID-19 mRNA疫苗的递送平台的显著成功，最近获得了很多关注。尽管如此，由mRNA诱导的瞬时蛋白表达的效用远远超出了对抗感染性疾病的疫苗-它们也有望成为癌症疫苗，蛋白质替代疗法和罕见遗传疾病的基因编辑组件。然而，裸mRNA固有地不稳定并且易于被核酸酶快速降解和自水解。LNPs包裹mRNA可以保护mRNA免受细胞外核糖核酸酶的侵害，并有助于细胞内mRNA的递送。在本报告中，我们讨论了LNPs用于RNA递送的核心特征。我们将注意力集中在设计用于递送mRNA的LNP上;然而，我们也包括siRNA-LNP递送的例子，以适当地突出由于核酸结构的共性和差异。首先，我们介绍了LNP的概念，利用核酸作为治疗剂的优点和缺点，以及LNP分子组成背后的一般推理。我们还简要强调了基于LNP的核酸疗法的最新临床成功。其次，介绍了LNP自组装的理论和方法。所有制备方法背后的共同思想是诱导核酸和带电脂质之间的静电相互作用，并通过疏水相互作用促进纳米颗粒生长。第三，我们分解了LNP的组成，特别注意每个组成部分的基本属性和目的。这包括确定的分子设计标准、商业来源、对细胞内运输的影响以及对LNP性质的贡献。LNP的关键组分之一是可电离脂质，其启动与内体膜的静电结合并促进胞质释放;然而，不应忽视其他脂质组分的作用，因为它们与LNP的稳定性、清除率和分布相关。第四，我们回顾了LNP构建体作为一个整体的属性，可以严重影响RNA的交付。这些属性是LNP大小、电荷、内部结构、脂质包装、脂质膜水合、稳定性和对生物大分子的亲和力。我们还讨论了用于检查这些属性的特定技术以及如何调整它们。最后，我们对RNA疗法的未来以及LNP制剂和优化领域中仍然存在的一些问题提出了我们的观点。
Lipid nanoparticles (LNPs) are a type of lipid vesicles that possess a homogeneous lipid core. These vesicles are widely used in small-molecule drug and nucleic acid delivery and recently gained much attention because of their remarkable success as a delivery platform for COVID-19 mRNA vaccines. Nonetheless, the utility of transient protein expression induced by mRNA extends far beyond vaccines against infectious diseases─they also hold promise as cancer vaccines, protein replacement therapies, and gene editing components for rare genetic diseases. However, naked mRNA is inherently unstable and prone to rapid degradation by nucleases and self-hydrolysis. Encapsulation of mRNA within LNPs protects mRNA from extracellular ribonucleases and assists with intracellular mRNA delivery.In this Account, we discuss the core features of LNPs for RNA delivery. We focus our attention on LNPs designed to deliver mRNA; however, we also include examples of siRNA-LNP delivery where appropriate to highlight the commonalities and the dissimilarities due to the nucleic acid structure. First, we introduce the concept of LNPs, the advantages and disadvantages of utilizing nucleic acids as therapeutic agents, and the general reasoning behind the molecular makeup of LNPs. We also briefly highlight the most recent clinical successes of LNP-based nucleic acid therapies. Second, we describe the theory and methods of LNP self-assembly. The common idea behind all of the preparation methods is inducing electrostatic interactions between the nucleic acid and charged lipids and promoting nanoparticle growth via hydrophobic interactions. Third, we break down the LNP composition with special attention to the fundamental properties and purposes of each component. This includes the identified molecular design criteria, commercial sourcing, impact on intracellular trafficking, and contribution to the properties of LNPs. One of the key components of LNPs is ionizable lipids, which initiate electrostatic binding with endosomal membranes and facilitate cytosolic release; however, the roles of other lipid components should not be disregarded, as they are associated with stability, clearance, and distribution of LNPs. Fourth, we review the attributes of LNP constructs as a whole that can heavily influence RNA delivery. These attributes are LNP size, charge, internal structure, lipid packing, lipid membrane hydration, stability, and affinity toward biomacromolecules. We also discuss the specific techniques used to examine these attributes and how they can be adjusted. Finally, we offer our perspective on the future of RNA therapies and some questions that remain in the realm of LNP formulation and optimization.