Figure 2.

Schematic illustration of key factors associated with the technology development of IVT-mRNA vaccines via the respiratory route. IVT-mRNA structural elements, including elongation of the poly(A) tail, the 5′ cap, the structure of UTRs, and the ORF with optional incorporation of modified nucleotides, are optimized to enhance the stability and reduce the innate immunogenicity. Nanoparticle-based carriers are designed to facilitate the delivery of IVT-mRNA across the barriers in the airway. Liquid aerosol or dry powderformulations are then developed with the identification of a suitable inhalation device (nebulizer or powder inhaler) for clinical applications. The aerosol performance, IVT-mRNA stability after aerosolization, immunogenicity, and vaccine efficacy of the inhaled formulation should be thoroughly characterized and evaluated.