Continuous and size-control synthesis of lipopolyplex nanoparticles enabled by controlled micromixing performance for mRNA delivery

IF 2 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Shirong Song, Zhikai Liu, Letao Guo, Wang Yao, Hongchen Liu, Mei Yang, Guangwen Chen
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Abstract

Accurate control of core–shell lipopolyplex nanoparticles (LPP NPs) size is crucial for finely adjusting their biomedical performance. However, the synthesis of LPP NPs encounters challenges as two mixing-sensitive processes are involved in the synthesis, rendering precise control over particle size difficult using conventional batch methods. In this study, the formation of the nucleic acid/cationic polymer cores through electrostatic complexation and the subsequent encapsulation by lipid shells via self-assembly were conducted in microreactors, with polyadenylic acid (poly A) and branched polyethylenimine (bPEI) employed as the model system. By assessing the micromixing performance of the microreactors using the Villermaux-Dushman method, the characteristic time scale for electrostatic complexation between poly A and bPEI, as well as the self-assembly of lipids, was determined to be below 1 ms. The Reynolds number, governing micromixing performance, emerged as a crucial factor influencing the sizes of poly A/bPEI cores and LPP NPs. In the kinetic control region, characterized by rapid mixing, the size of poly A/bPEI remained slightly influenced by the N/P molar ratio and volumetric flow rate ratio, irrespective of concentration. The zeta potential, however, was primarily affected by the N/P molar ratio. In the case of LPP NPs, under optimized conditions of anionic lipid molar ratio, the size of LPP NPs was significantly influenced by the composition of lipid shells. This study establishes the foundation for elucidating the structure–activity relationship of LPP NPs.

Abstract Image

利用可控微混合性能实现用于 mRNA 输送的脂质多聚物纳米颗粒的连续和尺寸可控合成
精确控制核壳脂质多聚物纳米粒子(LPP NPs)的尺寸对于精细调整其生物医学性能至关重要。然而,LPP NPs 的合成遇到了挑战,因为合成过程中涉及两个对混合敏感的过程,因此使用传统的批量方法很难精确控制粒度。本研究以聚腺嘌呤核酸(poly A)和支链聚乙烯亚胺(bPEI)为模型系统,在微反应器中通过静电络合形成核酸/阳离子聚合物核,随后通过自组装被脂质外壳包裹。通过使用 Villermaux-Dushman 方法评估微反应器的微混合性能,确定了聚 A 和 bPEI 之间的静电络合以及脂质自组装的特征时间尺度低于 1 毫秒。影响微混合性能的雷诺数是影响聚 A/bPEI 核心和 LPP NPs 尺寸的关键因素。在以快速混合为特征的动力学控制区域,聚 A/bPEI 的尺寸仍然受到 N/P 摩尔比和体积流量比的轻微影响,与浓度无关。但 zeta 电位主要受 N/P 摩尔比的影响。就 LPP NPs 而言,在阴离子脂质摩尔比的优化条件下,LPP NPs 的大小受到脂质外壳成分的显著影响。这项研究为阐明 LPP NPs 的结构-活性关系奠定了基础。
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来源期刊
Journal of Flow Chemistry
Journal of Flow Chemistry CHEMISTRY, MULTIDISCIPLINARY-
CiteScore
6.40
自引率
3.70%
发文量
29
审稿时长
>12 weeks
期刊介绍: The main focus of the journal is flow chemistry in inorganic, organic, analytical and process chemistry in the academic research as well as in applied research and development in the pharmaceutical, agrochemical, fine-chemical, petro- chemical, fragrance industry.
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