Harnessing a novel nematode protein for safe and specific RNA delivery to cells

利用新型线虫蛋白将 RNA 安全且特异性地递送至细胞

• 批准号: EP/Y037251/1
• 负责人: Amy Buck
• 金额: $ 16.19万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY037251%2F1
• 关键词: Harnessing; novel; nematode; protein; safe

RNA is a natural molecule that all organisms produce to instruct cells which proteins to make and also to regulate the amount of proteins that get made at different times and in different cells. There is increasing interest and capacity in designing RNAs to act as drugs to regulate protein expression in disease. Yet a major challenge is getting the RNA drugs delivered to the specific cells that need it, in a way that is safe and efficient. Our solution exploits the fact that some parasites have evolved their own RNA delivery systems in order to transfer their RNAs to mammalian cells and we have identified one natural RNA delivery protein that appears potent and simple to reconstitute. This is a novel nematode protein ("exWAGO") that nematodes release, in complex with RNA, which gets internalized by mouse intestinal epithelial cells (9, 10). Although first discovered in association with extracellular vesicles, we have data demonstrating that the recombinant protein itself gets taken up by mammalian cells and can be loaded with synthetic small RNAs (Fig. 1-2 below). Our aim here is to test the ability to design and load RNAs into the exWAGO protein to treat disease, with a focus on respiratory infections.

RNA是一个天然分子，所有生物体都会产生用于指导细胞制造的细胞，并调节在不同时间和不同细胞中生产的蛋白质量。设计RNA充当调节疾病中蛋白质表达的药物的兴趣和能力越来越多。然而，一个主要的挑战是将RNA药物递送到需要它的特定细胞，以安全有效的方式。我们的解决方案利用了这样一个事实，即某些寄生虫已经发展了自己的RNA递送系统以将其RNA转移到哺乳动物细胞上，并且我们已经确定了一种天然RNA递送蛋白，该蛋白似乎有效且易于重新构成。这是一种新型的线虫蛋白（“ exwago”），线虫与RNA复杂释放，它被小鼠肠上皮细胞内化（9，10）。尽管最初与细胞外囊泡相关，但我们有数据表明，重组蛋白本身被哺乳动物细胞吸收，并且可以加载合成的小RNA（下面的图1-2）。我们的目的是测试将RNA设计和加载到Exwago蛋白中以治疗疾病的能力，重点是呼吸道感染。