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

RNA是一种天然分子，所有生物体都会产生，以指示细胞合成哪些蛋白质，并调节在不同时间和不同细胞中合成的蛋白质的数量。人们对设计RNA作为药物来调节疾病中的蛋白质表达越来越感兴趣和越来越有能力。然而，一个主要的挑战是以安全和有效的方式将RNA药物运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，我们已经鉴定出一种天然的RNA递送蛋白，它似乎有效且易于重组。这是一种新的线虫蛋白(“exWAGO”)，由线虫释放，与RNA形成复合体，被小鼠肠道上皮细胞(9，10)内化。虽然最初是在细胞外小泡中发现的，但我们有数据表明，重组蛋白本身可以被哺乳动物细胞摄取，并可以装载合成的小RNA(图1-2)。我们在这里的目的是测试设计RNA并将RNA加载到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.