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Increasing secondary structure lengthens mRNA half-life, which, together with optimal codons, improves protein expression\n                    <jats:sup>5<\/jats:sup>\n                    . Therefore, a principled mRNA design algorithm must optimize both structural stability and codon usage. However, owing to synonymous codons, the mRNA design space is prohibitively large\u2014for example, there are around 2.4\u2009\u00d7\u200910\n                    <jats:sup>632<\/jats:sup>\n                    candidate mRNA sequences for the SARS-CoV-2 spike protein. This poses insurmountable computational challenges. Here we provide a simple and unexpected solution using the classical concept of lattice parsing\u00a0in computational linguistics, where finding the optimal mRNA sequence is analogous to identifying the most likely sentence among similar-sounding alternatives\n                    <jats:sup>6<\/jats:sup>\n                    . Our algorithm LinearDesign finds an optimal mRNA design for the spike protein in just 11 minutes, and can concurrently optimize stability and codon usage. LinearDesign substantially improves mRNA half-life and protein expression, and\u00a0profoundly increases antibody titre by up to 128 times in mice compared to the codon-optimization benchmark on\u00a0mRNA vaccines for\u00a0COVID-19 and varicella-zoster virus. This result reveals the great potential of principled mRNA design and enables the exploration of previously unreachable but highly stable and efficient designs. Our work is a timely tool for vaccines and other mRNA-based medicines encoding therapeutic proteins such as monoclonal antibodies and anti-cancer drugs\n                    <jats:sup>7,8<\/jats:sup>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41586-023-06127-z","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T12:02:13Z","timestamp":1683028933000},"page":"396-403","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":391,"title":["Algorithm for optimized mRNA design improves stability and immunogenicity"],"prefix":"10.1038","volume":"621","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-2167","authenticated-orcid":false,"given":"He","family":"Zhang","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1146-7848","authenticated-orcid":false,"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5662-1576","authenticated-orcid":false,"given":"Ang","family":"Lin","sequence":"additional","affiliation":[]},{"given":"Congcong","family":"Xu","sequence":"additional","affiliation":[]},{"given":"Ziyu","family":"Li","sequence":"additional","affiliation":[]},{"given":"Kaibo","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Boxiang","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Xiaopin","family":"Ma","sequence":"additional","affiliation":[]},{"given":"Fanfan","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Huiling","family":"Jiang","sequence":"additional","affiliation":[]},{"given":"Chunxiu","family":"Chen","sequence":"additional","affiliation":[]},{"given":"Haifa","family":"Shen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-2703","authenticated-orcid":false,"given":"Hangwen","family":"Li","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-6557","authenticated-orcid":false,"given":"David H.","family":"Mathews","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7450-2642","authenticated-orcid":false,"given":"Yujian","family":"Zhang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6444-7045","authenticated-orcid":false,"given":"Liang","family":"Huang","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,5,2]]},"reference":[{"key":"6127_CR1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1056\/NEJMoa2035389","volume":"384","author":"LR Baden","year":"2021","unstructured":"Baden, L. 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