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Rational preparation and application of a mRNA delivery system with cytidinyl/cationic lipid
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2021-10-23 , DOI: 10.1016/j.jconrel.2021.10.023
Lei Li 1 , Jinrong Long 2 , Ye Sang 3 , Xin Wang 1 , Xinyang Zhou 4 , Yufei Pan 4 , Yiming Cao 5 , Huiyuan Huang 6 , Zhenjun Yang 4 , Jing Yang 1 , Shengqi Wang 1
Affiliation  

The messenger RNA (mRNA)-based therapy, especially mRNA vaccines, has shown its superiorities in versatile design, rapid development and scale production, since the outbreak of coronavirus disease 2019 (COVID-19). Although the Pfizer-BioNTech and Moderna COVID-19 mRNA vaccines had been approved for application, unexpected adverse events were reported to be most likely associated with the mRNA delivery systems. Thus, the development of mRNA delivery system with good efficacy and safety remains a challenge. Here, for the first time, we report that the neutral cytidinyl lipid, 2-(4-amino-2-oxopyrimidin-1-yl)-N-(2,3-dioleoyl-oxypropyl) acetamide (DNCA), and the cationic lipid, dioleoyl-3,3′-disulfanediylbis-[2-(2,6-diaminohexanamido)] propanoate (CLD), could encapsulate and deliver the COVID-19 mRNA-1096 into the cytoplasm to induce robust adaptive immune response. In the formulation, the molar ratio of DNCA/CLD to a single nucleotide of COVID-19 mRNA-1096 was about 0.9: 0.5: 1 (the N/P ratio was about 7: 1). The DNCA/CLD-mRNA-1096 lipoplexes were rationally prepared by the combination of the lipids DNCA/CLD with the aqueous mRNA solution under mild sonication to stimulate multiple interactions, including H-bonding, π-stacking and electrostatic force between the lipids and the mRNA. After intramuscular applications of the DNCA/CLD-mRNA-1096 lipoplexes, robust neutralizing antibodies and long-lived Th1-biased SARS-CoV-2-specific cell immunity were detected in the immunized mice, thus suggesting the DNCA/CLD a promising mRNA delivery system. Moreover, our study might also inspire better ideas for developing mRNA delivery systems.



中文翻译:

胞苷基/阳离子脂质mRNA递送系统的合理制备与应用

自 2019 年冠状病毒病 (COVID-19) 爆发以来,基于信使 RNA (mRNA) 的疗法,尤其是 mRNA 疫苗,已显示出其在通用设计、快速开发和规模生产方面的优势。尽管 Pfizer-BioNTech 和 Moderna COVID-19 mRNA 疫苗已获批应用,但据报道,意想不到的不良事件很可能与 mRNA 递送系统有关。因此,开发具有良好疗效和安全性的 mRNA 递送系统仍然是一个挑战。在这里,我们首次报道了中性胞苷基脂质 2-(4-amino-2-oxopyrimidin-1-yl)-N-(2,3-dioleoyl-oxypropyl) acetamide (DNCA) 和阳离子脂质,二油酰-3,3'-二硫二基双-[2-(2,6-二氨基己酰胺基)]丙酸酯(CLD),可以封装 COVID-19 mRNA-1096 并将其递送到细胞质中,以诱导强烈的适应性免疫反应。配方中DNCA/CLD与COVID-19 mRNA-1096单核苷酸的摩尔比约为0.9:0.5:1(N/P比约为7:1)。DNCA/CLD-mRNA-1096 脂质复合物是通过将脂质 DNCA/CLD 与 mRNA 水溶液在温和超声处理下结合合理制备的,以刺激脂质与脂质之间的多重相互作用,包括氢键、π-堆积和静电力。 mRNA。在肌肉注射 DNCA/CLD-mRNA-1096 脂质复合物后,在免疫小鼠中检测到强大的中和抗体和长寿命的 Th1 偏向性 SARS-CoV-2 特异性细胞免疫,从而表明 DNCA/CLD 是一种有前途的 mRNA 递送系统。而且,

更新日期:2021-10-31
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