Mucosal IFNλ1 mRNA-based immunomodulation effectively reduces SARS-CoV-2 induced mortality in mice

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• RNA vaccines demonstrate efficacy against SARS-CoV-2.
• The potential of mRNA as an antiviral immunotherapeutic remains largely unexplored.
• Interferon lambda 1 (IFNλ1) is crucial for innate immunity at mucosal surfaces against viral infections.

Purpose of the Study:

• To investigate the antiviral activity of lipidoid nanoparticle (LNP)-formulated mRNA encoding human IFNλ1 (ETH47).
• To evaluate the efficacy of pulmonary IFNλ1 mRNA administration in a mouse model of SARS-CoV-2 infection.

Main Methods:

• Formulation of mRNA encoding human IFNλ1 (ETH47) in lipidoid nanoparticles (LNPs).
• In vitro assessment of protein translation, interferon-stimulated gene induction, and SARS-CoV-2 replication inhibition.
• In vivo evaluation of pulmonary IFNλ1 mRNA administration in mice challenged with SARS-CoV-2.

Main Results:

• IFNλ1 mRNA administration demonstrated dose-dependent protein translation and inhibition of SARS-CoV-2 replication in vitro.
• Pulmonary administration of IFNλ1 mRNA in mice led to reduced viral load, decreased body weight loss, and increased survival.
• The treatment induced interferon-stimulated genes without significant non-specific immune stimulation.

Conclusions:

• Inhaled IFNλ1 mRNA is a potent antiviral strategy against SARS-CoV-2.
• This approach holds potential as a prophylactic or therapeutic option for COVID-19.
• IFNλ1 mRNA therapy may be applicable to other respiratory viral infections and pandemic preparedness.