Therapeutic intranasal delivery of NanoSTING provides broad protection against seasonal and highly pathogenic influenza strains.

Influenza is a major global threat due to several factors, including great zoonotic potential, ongoing antigenic drift, limited effectiveness of current vaccines, and the emergence of drug-resistant viral strains. Broad-spectrum therapeutic regimens that can treat vulnerable populations, enable faster resolution of symptoms, and decrease fatality rates are a long-sought objective for influenza. Here, we report the development of NanoSTING, a liposomally encapsulated STING agonist (cGAMP), as a single-dose intranasal treatment of influenza. We demonstrate that NanoSTING is stable under simple refrigeration conditions, with no loss of encapsulated cGAMP, for up to a year. A single dose of NanoSTING administered intranasally induced robust type I interferon responses in the nasal and lung tissue of mice without observable toxicity. In mouse challenge models of influenza A (H1N1 or highly pathogenic H5N1) and influenza B, NanoSTING provided therapeutic protection at least as effective as ten doses of oseltamivir. NanoSTING demonstrated therapeutic efficacy even when administered 48-72 h post-infection. Furthermore, NanoSTING maintained its activity in aged and immunocompromised mice, as evidenced by the robust induction of interferon responses in nasal tissues, highlighting its potential for use in vulnerable individuals. These attributes of NanoSTING support its potential use as a promising host-directed anti-viral with a large therapeutic window and broad-spectrum efficacy.