SARS-CoV-2 has emerged on the world stage as a highly infectious agent that can spread rapidly geographically and has a case fatality rate of ~2-3.0%. Several vaccine candidates against SARS-CoV-2 are being developed. However, these may take a year or more to generate and to undergo field testing for safety and efficacy, and will not help those already infected with the virus. There are a number of studies looking at repurposing of old drugs and aim to reduce viral growth in order to alter clinical outcomes in the very sick, or to prophylactically treat front line workers. None are coronavirus specific and their effectiveness at this time is at best controversial. SARS-CoV-2 siRNAs can be developed rapidly due to our previous work on respiratory viruses and drug delivery. Moreover, siRNAs can be used both prophylactically and therapeutically. To date, there is nothing reported on the use of siRNAs to treat SARS-CoV-2. Hence, we carried out a screen of siRNAs targeted SARS-CoV-2. We showed that a number of siRNAs could prophylactically reduce viral infectivity in Vero E6 cells. Moreover, our siRNAs exhibited little to no immmuno-stimulatory effect on THP-1 macrophages. Using our previously developed stealth nanoparticle delivery system, which is able to deliver siRNAs to the lung via the bloodstream, we are currently conducting experiments to deliver our top candidate anti-SARS-CoV-2 siRNAs intoSARS-CoV-2-infected hACE2 mice. We predict that our encapsulated SARS-CoV-2 siRNAs can provide robust inhibition of viral infectivity in vivo. These in vivo studies will establish the proof-of-concept for our strategy to deliver anti-SARS-CoV-2 siRNAs to the lungs of infected individuals to repress virus expression and COVID-19 disease. The innovative approach we propose here will target SARS-CoV-2 with single or even multi-targeted siRNAs which enhances potency and limits the potential for the virus to evolve resistance.