A synthetic virus-like assembly unlocks dual-antigen presentation for broad-spectrum anti-SARS-CoV-2 immunity

Abstract In the present study, by building on the previous development of a DC-SIGN-targeting virus-like structure (VLS) vaccine platform and a comprehensive characterization of SARS-CoV-2 structural biology, particularly insights into the role of the nucleocapsid (N) protein in eliciting cytotoxic T lymphocyte (CTL) responses during infection, we designed a SARS-CoV-2 virion-mimetic structural vaccine that encapsulates an mRNA encoding the spike S1 antigen complexed with N protein complexes, with S1 proteins loaded on its surface. This characterized virion-mimetic structural vaccine not only induces the production of high-efficiency antibodies against both the spike and N proteins but also elicits robust S1-specific and N-specific CTL responses in animal models. Furthermore, the generated antibodies exhibit cross-reactive neutralizing activity against multiple SARS-CoV-2 variants and provide protective immunity against challenge with mutant viruses in immunized hosts. This SARS-CoV-2 virion-mimetic structure effectively recapitulates natural infection pathways, comprehensively activating the innate immune system and thereby creating an optimal microenvironment for eliciting potent and broad-spectrum adaptive immune responses.