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

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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.