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Using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model system, we genetically fused a stabilized variant of the Wuhan-Hu-1 spike protein receptor binding domain (RBD) to a protein nanoparticle we previously designed for optimal secretion from human cells. Upon secretion, the nanoparticle formed monodisperse and antigenically intact assemblies displaying 60 copies of the RBD in an immunogenic array. Compared with mRNA vaccines encoding membrane-anchored spike protein and a secreted RBD trimer, an mRNA vaccine encoding the RBD nanoparticle elicited 5- to 28-fold higher titers of neutralizing antibodies in mice. In addition, the \u201cmRNA-launched\u201d RBD nanoparticle vaccine induced higher frequencies of antigen-specific CD8 T cells than the same immunogen delivered as adjuvanted protein and protected mice from either Wuhan-Hu-1 or Omicron BA.5 challenge. These results establish that delivering computationally designed protein nanoparticle immunogens through mRNA can combine the benefits of both vaccine modalities. More broadly, our data highlight the utility of computational protein design in genetic vaccination strategies.<\/jats:p>","DOI":"10.1126\/scitranslmed.adu2085","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:58:27Z","timestamp":1760551107000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":22,"title":["Computationally designed mRNA-launched protein nanoparticle immunogens elicit protective antibody and T cell responses in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5844-1403","authenticated-orcid":true,"given":"Grace G.","family":"Hendricks","sequence":"first","affiliation":[{"name":"Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"name":"Department of Biochemistry, University of Washington, Seattle, WA 98195, 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