Nucleic acid-based vaccines are leading-edge tools in developing next-generation preventative care. Much research has been done to convert vaccine gene therapy from an invasive to a noninvasive administration approach. The lung's large surface area and permeability make the pulmonary route a promising noninvasive delivery option for vaccines, with systemic and local applications. This review summarizes the challenges and the approaches that have been carried out to optimize the delivery of nucleic acids through the pulmonary route for vaccination purposes in recent years, with a spotlight on gold nanoparticles (AuNPs). Nonviral delivery systems have been widely explored, and AuNPs with their unique properties are emerging as promising tools for nucleic acid vaccines due to surface functionalization with mucus-penetrating polymers and targeting moieties that can bypass the barriers in pulmonary delivery and successfully deliver nucleic acids to the cells of interest. However, while promising, several challenges remain including selectively overcoming the lungs' immunological surveillance and adhesive mucus.
