Science translational medicineOct 15, 2025

Computer-designed mRNA-made protein nanoparticles trigger protective antibody and T cell responses in mice

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

An mRNA-launched SARS-CoV-2 protein nanoparticle vaccine produced stronger immune responses and protection in mice than comparator vaccine formats.

Evidence

This preclinical vaccine study showed that an mRNA-encoded RBD nanoparticle formed intact 60-copy assemblies, elicited 5- to 28-fold higher neutralizing antibody titers in mice, increased antigen-specific CD8 T cells versus adjuvanted protein, and protected against Wuhan-Hu-1 or Omicron BA.5 challenge.

Caveat

The work is a mouse proof-of-concept using SARS-CoV-2 as a model system, so durability, human immunogenicity, and broader vaccine performance are not established here.

Simplified

Messenger RNA (mRNA) vaccines and computationally designed protein nanoparticle vaccines were both clinically derisked and licensed for the first time during the coronavirus disease 2019 (COVID-19) pandemic. These vaccine modalities have complementary immunological benefits that provide strong motivation for their combination. Here, we demonstrate proof of concept for genetic delivery of computationally designed protein nanoparticle immunogens. 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 "mRNA-launched" 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.