Leveraging mRNA Sequences and Nanoparticles to Deliver SARS‐CoV‐2 Antigens In Vivo

Abstract SARS‐CoV‐2 has become a pandemic worldwide; therefore, an effective vaccine is urgently needed. Recently, messenger RNAs (mRNAs) have emerged as a promising platform for vaccination. In this work, the untranslated regions (UTRs) of mRNAs are systematically engineered in order to enhance protein production. Through a comprehensive analysis of endogenous gene expression and de novo design of UTRs, the optimal combination of 5′ and 3′ UTR are identified and termed NASAR, which are 5‐ to 10‐fold more efficient than the tested endogenous UTRs. More importantly, NASAR mRNAs delivered by lipid‐derived TT3 nanoparticles trigger a dramatic expression of potential SARS‐CoV‐2 antigens. The antigen‐specific antibodies induced by TT3‐nanoparticles and NASAR mRNAs are over two orders of magnitude more than that induced by the FDA‐approved lipid nanoparticle material MC3 in vaccinated mice. These NASAR mRNAs merit further development as alternative SARS‐CoV‐2 vaccines.