DNA‐Engineered Modular Nanovaccines Featuring Precise Topology for Enhanced Immunogenicity

Abstract Multivalent display of antigens can boost subunit vaccine immunogenicity. However, owing to the inherent difficulty in programmatically controlling the topology of multivalent antigens, its impact on antigen immunogenicity remains elusive. In this study, DNA‐mediated modular precision assembly is employed to organize SARS‐CoV‐2 receptor‐binding domains (RBDs) with different topological connections while preserving their epitopes. It is found that branching‐connected RBDs induced significantly higher IgG titers than linear‐connected RBDs at higher antigen valency (≥4). This increase in IgG response is associated with stronger B cell proliferation, likely due to enhanced antigen‐receptor synergistic interactions leading to enhanced B cell receptor signaling. Branching‐connected RBDs also provided superior humoral immunity in mice and stronger protection in SARS‐CoV‐2‐infected hamsters compared to adjuvanted RBD. This work highlights the role of antigen topology in vaccine design and offers a universal modular platform for producing more effective subunit vaccines.