Inhalation Delivery of Interferon-λ-Loaded Pulmonary Surfactant Nanoparticles Induces Rapid Antiviral Immune Responses in the Lung

Abstract

The interferon-lambda (IFN-lambda)-regulated innate immune responses in the airway expand our understanding toward antiviral strategies against influenza A virus (IAV). The application of IFN-lambda as mucosal antiviral therapeutic is still challenging, and advanced research will be necessary to achieve more efficient delivery of recombinant IFN-lambda s to the damaged respiratory mucosa. In this study, we examine the capability of IFN-lambda to stimulate the innate immune response, promoting the swift elimination of IAV in the lungs. Additionally, we develop IFN-lambda-loaded nanoparticles incorporated into pulmonary surfactant for inhalation therapy aimed at treating lung infections caused by IAV. We found that inhaled delivery of IFN lambda-PSNPs significantly restricted IAV replication in the lungs from 3 days after infection (dpi), and IAV-caused lung histopathologic findings were completely improved in response to IFN lambda-PSNPs. More significant and rapid attenuation of viral RNA was observed in the lung of mice with inhaled delivery of IFN lambda-PSNPs compared to mice with recombinant IFN-lambda s. Inhalation treatment of IFN lambda-PSNPs to IAV-infected mice can result in the increase of monocyte frequency in concert with restoration of T and B cells composition. Furthermore, the transcriptional profiles of monocytes shifted toward heightened IFN responses following IFN lambda-PSNP treatment. These results imply that IFN-lambda could serve as a robust inducer of innate immunity in the lungs against IAV infection, and inhalation of IFN-lambda s encapsulated in PSNPs effectively resolves lung infections caused by IAV through rapid viral clearance. PSNPs facilitated improved delivery of IFN-lambda s to the lungs, triggering potent antiviral immune responses upon IAV infection onset.