Engineering a Virus-like Nanovaccine for Durable and Potent Antigen-Specific Adoptive Immunity

The topological characteristics of microbial surfaces play pivotal roles in immune responses. However, integrating adjuvants and antigens to construct nanovaccines that mimic pathogenic surface nanostructures, especially for antigen delivery and immune activation, remains unexplored. Herein, we systematically investigated the antigen delivery efficiency and immunostimulatory capacity of nanovaccines with distinct morphologies: MO@SP (spherical), MO@ST (fibrous), MO@LA (lamellar), and MO@VLP (rough-surfaced spiky-like), synthesized through the self-assembly of manganese ions (Mn2+) with antigen peptides. These nanovaccines were designed to evaluate their potential for efficient antigen delivery and immune activation, with a particular focus on how their structural properties influence cellular uptake and immunogenicity. Among the different morphologies, MO@VLP exhibited superior internalization by dendritic cells (DCs) via caveolae-dependent endocytosis and F-actin-mediated pathways, followed by efficient lysosomal escape and antigen release into the cytoplasm, facilitating antigen cross-presentation due to its distinctive spike-like structure. Notably, MO@VLP, akin to viral surfaces, induced cytoskeletal rearrangement and activated Toll-like receptor (TLR) signaling pathway, ultimately leading to DC maturation. Moreover, MO@VLP markedly enhanced nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) inflammatory signaling, promoting strong tumor-specific immune responses. Compared to nanovaccines with other morphologies, MO@VLP showed significantly enhanced tumor-preventive efficacy in the B16-OVA tumor model. Meanwhile, in combination with immune checkpoint blockade (ICB) therapy, MO@VLP provoked potent antigen-specific cellular immune responses, significantly suppressed tumor growth, and extended survival to 67 days in murine models. This study underscores the structure-dependent effects of metal-coordinated antigenic nanoarchitectures in immune activation and highlights the potential of adjuvant-functionalized, spike-mimetic nanovaccines for cancer immunotherapy.