A Modular Biomimetic Nanovaccine for TBEV: Orchestrating Cascade Immunoprotection via Programmed Dendritic Cell Targeting and Antigen–Adjuvant Co-delivery

Abstract Tick-borne encephalitis (TBE) is an escalating global health threat, increasingly exacerbated by climate change, and underscores the need for innovative vaccine strategies. Conventional subunit vaccines are limited by suboptimal spatiotemporal dissociation between antigens and adjuvants, as well as insufficient specific targeting, resulting in compromised immunogenicity. Herein, we report a biomimetic nanovaccine platform engineered to overcome these limitations through the synergistic co-delivery of antigen and adjuvant. This platform is constructed by co-displaying the TBE virus envelope protein domain III (fused to a dendritic cell-targeting peptide, Dcpep) together with the molecular adjuvant MAB2560 on the surface of bacterium-like particles (BLPs). The resulting co-display vaccine, EDc2&MAB2560-GEM BLPs, outperforms a simple mixture of its components, inducing significantly higher titers of TBEV-specific IgG antibodies, robust T-cell and B-cell immune responses, and durable immunity in mice. Mechanistic studies reveal that these enhanced immune responses arise from the platform’s ability to precisely co-deliver antigen and adjuvant to dendritic cells, thereby triggering a potent cascading immunostimulatory effect. This work highlights the critical role of spatiotemporal coupling within targeted nanocarriers and establishes a versatile strategy for the development of next-generation subunit vaccines with enhanced potency and safety.