Anew messenger RNA (mRNA) design tool addresses two significant obstacles to the therapeutic use of mRNA: effective protein expression and structural stability.

The COVID-19 pandemic brought a breakthrough in the medicinal use of mRNA. The emerging and rapidly developing field of RNA medicine also includes using mRNA to deliver therapeutic antibodies and anti-cancer drugs. However, clinical use of mRNA is challenging because of the low stability of mRNA molecules, the need for effective expression of therapeutic proteins from mRNA, and the need for modulating the immune response to foreign RNA. Because a codon of three adjacent nucleotides encodes each amino acid, and because of redundancies in this genetic code, the number of candidate mRNA molecules for expressing a given protein is vast and unsearchable with conventional tools.

A recent report in Nature provides a new mRNA design tool that considers both the need for optimal codon usage for protein expression and structural stability. The new mRNA design tool identified mRNA candidates for expressing the SARS-CoV-2 Spike protein. The use of the tool may extend to most real world applications of mRNA, and may even be relevant for the nucleotide editing tool CRISPR-Cas or self-amplifying RNA.

Our algorithm LinearDesign takes only 11 minutes for the Spike protein, and can jointly optimize stability and codon usage. On both COVID-19 and varicella-zoster virus mRNA vaccines, LinearDesign substantially improves mRNA half-life and protein expression, and dramatically increases antibody titer by up to 128× in vivo, compared to the codon-optimization benchmark.

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