There is an urgent need to expand the arsenal of preventative options against SARS-CoV-2. We envision a new type of prophylaxis based on intranasal administration of siRNAs. To this end, we developed a framework called Sens.AI to find hyper-potent RNAi triggers. Sens.AI relies on a cost-effective massively parallel assay based on Twist Oligo Pools. We used Sens.AI to screen >16,000 RNAi triggers against SARS-CoV-2, testing virtually every amenable site in the virus genome. After validating the quality of our screen, we selected 10 promising siRNAs for further experimentation. Five triggers exhibited IC50<20pM and repressed the virus by more than 95% in vitro, including the Delta strain. Encouraged by these results, we tested the prophylaxis activity of our cocktail in a hamster model and found that it significantly protected against infection compared to a negative control and exhibits similar results to the FDA-authorized Bamlanivimab.