A universal intranasal nanoengineered therapy against airborne RNA viruses

PROJECT SUMMARY The past two decades have witnessed several air-borne viruses (SARS-CoV1, MERS, SARS- CoV2) that led to significant mortality. There is always a lag time before a vaccine is introduced. This lag creates an urgent need for a universal antiviral therapy that can be deployed rapidly as a prophylactic measure. Here, we propose to address this gap by engineering a novel intranasal- delivered nanoparticle that exerts an universal antiviral effect by activating a unique evolution- encoded innate immune state in nasal epithelial cells to provide early protection. There is a strong rationale for targeting nasal epithelium for an antiviral prophylaxis for air-borne viruses: (1) Nasal epithelium is the most common portal of entry of these pathogens; (2) The nasal cavity and nasopharynx contain some of the highest viral loads; and (3) Neutralizing the virus in the nasal epithelium has been shown to not only decrease viral load in both the nasal cavity and in distant sites, but potentially reduce transmission from asymptomatic individuals. While these studies validate nasal delivery as an ideal route of administration for viral prophylaxis, an effective universal antiviral therapy remains an unmet need. We hypothesize that activating an evolutionary conserved antiviral mechanism, i.e. the induction of IFN-Induced proteins with tetratricopeptide repeats 1 (IFIT1), can emerge as an effective universal prophylaxis against airborne viruses. This can be achieved by inhibiting CMTR2, a novel target, in the nasal epithelium. We will: (Aim 1) Engineer antiViral Response-Activating Nanoparticles (V-RANs) for intranasal delivery and test for inhibition of CMTR2 and induction of IFIT1; (Aim 2) Evaluate the antiviral efficacy and safety of V- RANs in mouse models of severe SARS coronavirus or pandemic flu infections; and in (Aim 3) Elucidate the molecular mechanism of V-RAN-induced antiviral response. Published reports and our preliminary results demonstrate the feasibility of this project. This study can lead to new insights into intranasal nanodelivery, and a novel antiviral prophylaxis that can shift the paradigm for early interventions in future pandemics.