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

RNA是一种所有生物体都能产生的天然分子，它能指导细胞合成蛋白质，并调节不同时间、不同细胞中合成的蛋白质数量。设计RNA作为药物来调节疾病中的蛋白质表达的兴趣和能力越来越大。然而，一个主要的挑战是以安全有效的方式将RNA药物递送到需要它的特定细胞。我们的解决方案利用了这样一个事实，即一些寄生虫已经进化出自己的RNA递送系统，以便将它们的RNA转移到哺乳动物细胞中，并且我们已经鉴定出一种天然的RNA递送蛋白，其似乎是有效的并且易于重组。这是线虫释放的一种新的线虫蛋白（“exWAGO”），与RNA复合，被小鼠肠上皮细胞内化（9，10）。虽然首次发现与细胞外囊泡相关，但我们有数据表明重组蛋白本身被哺乳动物细胞吸收，并可以装载合成的小RNA（图1-2）。我们的目标是测试设计和加载RNA到exWAGO蛋白中以治疗疾病的能力，重点是呼吸道感染。

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.