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Mosaic nanoparticle vaccines with heterotypic antigens exhibit broad‐spectrum antiviral capabilities, but the impact of antigen proportions and distribution patterns on vaccine‐induced immunity remains largely unexplored. Here, we present a DNA nanotechnology‐based strategy for spatially assembling heterotypic antigens to guide the rational design of mosaic nanoparticle vaccines. By utilizing two aptamers with orthogonal selectivity for the original SARS‐CoV‐2 spike trimer and Omicron receptor‐binding domain (RBD), along with a DNA soccer‐ball framework, we precisely manipulate the spacing, stoichiometry, and overall distribution of heterotypic antigens to create mosaic nanoparticles with average, bipolar, and unipolar antigen distributions. Systematic in vitro and in vivo immunological investigations demonstrate that 30 heterotypic antigens in equivalent proportions, with an average distribution, lead to higher production of broad‐spectrum neutralizing antibodies compared to the bipolar and unipolar distributions. Furthermore, the precise assembly utilizing our developed methodology reveals that a mere increment of five Omicron RBD antigens on a nanoparticle (from 15 to 20) not only diminishes neutralization against the Omicron variant but also triggers excessive inflammation. This work provides a unique perspective on the rational design of mosaic vaccines by highlighting the significance of the spatial placement and proportion of heterotypic antigens in their structure–activity mechanisms. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 mutates rapidly as evidenced by the emergence of Omicron which causes changes in the recognition epitopes of most current neutralizing antibodies and immune evasion. Although aptamers are potential neutralizing agents for SARS-CoV-2 due to their unique molecular properties, it is difficult to compare their performances as assay conditions vary greatly, and their activity levels against variants remain unknown. Here, we evaluated the performances of 14 SARS-CoV-2 aptamers and provided a comprehensive analysis them, which we expect will improve the development of aptamer tools for SARS-CoV-2 diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]