Morphology evolution of lipid nanoparticle discovered by small angle neutron scattering

IF 5.4 1区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY GIANT Pub Date : 2024-07-25 DOI:10.1016/j.giant.2024.100329
Yuqing Li , Changli Ma , Zehua Han , Weifeng Weng , Sicong Yang , Zepeng He , Zheqi Li , Xiaoye Su , Taisen Zuo , He Cheng
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Abstract

The structure of mRNA lipid nanoparticles (LNPs) is still under debate, with different studies presenting varying morphological characteristics, significantly hindering their biomedical potential. A typical formulation process of mRNA LNPs involves three steps: initial rapid mixing of lipids in an ethanol phase and mRNA in an acidic aqueous phase, followed by the swift removal of ethanol, and finally adjusting the solution to a neutral environment. In this study, we utilize Small Angle Neutron Scattering (SANS) with contrast matching to reveal the kinetic pathway-dependent of mRNA LNPs morphology. We find that the formulation process of the Moderna COVID-19 vaccine is controlled by a competition between aggregation and microphase separation, dictating the diverse morphologies observed in mRNA LNPs. The first step leads to the formation of polydisperse spherical droplets with an average diameter of 42±6.0 nm in an acidic ethanol aqueous solution. Ethanol removal initiates both aggregation and internal microphase separation, resulting in a polydisperse core-shell structure with an average diameter of 48±3.7 nm. Heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy) hexyl) amino) octanoate (SM-102) binds to mRNA via electrostatic interaction to form a reverse-wormlike micelle structure inside. The 1,2-Distearoyl-sn‑glycero-3-phosphocholine (DSPC) and PEG-lipid are just in the shell and cholesterol acting as a filler throughout the core-shell structure. Upon transitioning to a neutral environment, SM-102 loses its charge and neither the periphery nor the reverse-wormlike micelle can maintain their stabilities, leading to further aggregation and microphase separation. The average diameter of core-shell structure turns to be 66±5.2 nm. In the actual formulation process of the Moderna COVID-19 vaccine, steps 2 and 3 occur simultaneously, and the competition between aggregation and microphase separation determines the final morphology. These findings offer crucial insights into optimizing the morphology of mRNA LNPs, thereby facilitating advancements in vaccine development and mRNA vaccine delivery technologies.

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小角中子散射发现脂质纳米粒子的形态演变
关于 mRNA 脂质纳米粒子(LNPs)的结构仍存在争议,不同的研究呈现出不同的形态特征,极大地阻碍了其生物医学潜力的发挥。mRNA LNPs 的典型配制过程包括三个步骤:首先将乙醇相中的脂质与酸性水相中的 mRNA 快速混合,然后迅速去除乙醇,最后将溶液调整至中性环境。在本研究中,我们利用小角中子散射(SANS)与对比度匹配揭示了 mRNA LNPs 形态的动力学路径依赖性。我们发现,Moderna COVID-19 疫苗的配制过程受控于聚集和微相分离之间的竞争,这决定了在 mRNA LNPs 中观察到的不同形态。第一步是在酸性乙醇水溶液中形成平均直径为 42±6.0 nm 的多分散球形液滴。移除乙醇后,会产生聚集和内部微相分离,从而形成平均直径为 48±3.7 nm 的多分散核壳结构。Heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy) hexyl) amino) octanoate(SM-102)通过静电作用与 mRNA 结合,在内部形成反向蠕虫状胶束结构。1,2-二硬脂酰-sn-甘油-3-磷酸胆碱(DSPC)和 PEG-脂质只是在外壳中,胆固醇在整个核壳结构中充当填充物。在过渡到中性环境时,SM-102 会失去电荷,外围和反向蠕虫状胶束都无法保持稳定,导致进一步聚集和微相分离。核壳结构的平均直径为 66±5.2 nm。在 Moderna COVID-19 疫苗的实际配制过程中,第 2 步和第 3 步同时进行,聚集和微相分离之间的竞争决定了最终的形态。这些发现为优化 mRNA LNPs 的形态提供了重要启示,从而促进了疫苗开发和 mRNA 疫苗递送技术的进步。
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来源期刊
GIANT
GIANT Multiple-
CiteScore
8.50
自引率
8.60%
发文量
46
审稿时长
42 days
期刊介绍: Giant is an interdisciplinary title focusing on fundamental and applied macromolecular science spanning all chemistry, physics, biology, and materials aspects of the field in the broadest sense. Key areas covered include macromolecular chemistry, supramolecular assembly, multiscale and multifunctional materials, organic-inorganic hybrid materials, biophysics, biomimetics and surface science. Core topics range from developments in synthesis, characterisation and assembly towards creating uniformly sized precision macromolecules with tailored properties, to the design and assembly of nanostructured materials in multiple dimensions, and further to the study of smart or living designer materials with tuneable multiscale properties.
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