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Self-amplifying Replicon RNA delivery to Dendritic Cells by Cationic Lipids
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-05-04
Pavlos C. Englezou, Cedric Sapet, Thomas Démoulins, Panagiota Milona, Thomas Ebensen, Kai Schulze, Carlos-Alberto Guzman, Florent Poulhes, Olivier Zelphati, Nicolas Ruggli, Kenneth C. McCullough

Advances in RNA technology during the past two decades have led to the construction of replication-competent RNA termed replicons, RepRNA or self-amplifying mRNA with high potential for vaccine applications. Cytosolic delivery is essential for their translation and self-replication - without infectious progeny generation - providing high levels of antigen expression for inducing humoral and cellular immunity. Synthetic nanoparticle-based delivery vehicles can both protect the RNA molecules and facilitate targeting of dendritic cells – critical for immune defence development. Several cationic lipids were assessed with RepRNA generated from classical swine fever virus encoding nucleoprotein genes of influenza A virus. The non-cytopathogenic nature of the RNA allowed targeting to dendritic cells without destroying the cells – important for prolonged antigen production and presentation. Certain lipids were more effective at delivery and at promoting translation of RepRNA than others. Selection of particular lipids provided delivery to dendritic cells that did result in translation, demonstrating that delivery efficiency could not guarantee translation. The observed translation in vitro was reproduced in vivo by inducing immune responses against the encoded influenza virus antigens. Cationic lipid-mediated delivery shows potential for promoting RepRNA vaccine delivery to dendritic cells, particularly if combined with additional delivery elements.



中文翻译:

通过阳离子脂质自扩增复制子RNA传递至树突状细胞

在过去的二十年里,RNA技术的进步导致了具有复制能力的RNA的构建,这种复制蛋白被称为复制子,RepRNA或具有自我扩增潜力的mRNA,具有很高的疫苗应用潜力。胞质传递对于它们的翻译和自我复制是必不可少的-没有感染后代的产生-提供高水平的抗原表达以诱导体液和细胞免疫。基于合成纳米粒子的运载工具既可以保护RNA分子,又可以促进针对树突状细胞的靶向,这对于免疫防御系统的发展至关重要。用编码经典甲型流感病毒核蛋白基因的猪瘟病毒产生的RepRNA评估了几种阳离子脂质。RNA的非致细胞病变性质使其可以靶向树突状细胞而不会破坏细胞,这对于延长抗原的产生和呈递非常重要。某些脂质比其他脂质在递送和促进RepRNA的翻译方面更有效。特定脂质的选择提供了确实导致翻译的向树突细胞的递送,这表明递送效率不能保证翻译。观察到的翻译通过诱导针对编码的流感病毒抗原的免疫应答,在体外复制了体外。阳离子脂质介导的递送显示出促进RepRNA疫苗递送至树突状细胞的潜力,特别是如果与其他递送元素结合使用时。

更新日期:2018-05-04
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