Although injectable respiratory syncytial virus (RSV) pre-F vaccines are clinically established, effective intranasal alternatives remain elusive. Geometric and surface antigen display properties are critical for respiratory B cell activation, yet lack strategies for systematic optimization. Here we report a library of DNA nanocarriers with controlled dimensions and sizes, aiming to systemically evaluate the influence of geometric properties on intranasal retention. Taking advantage of the precise control on DNA nanocarriers and antigen functionalization, we organized the surface antigen patterns of pre-F monomers on DNA nanocarriers to maximize B cell activation. The optimized DNA nanocarrier-based vaccine elicited humoral immunity in mice comparable to that induced by the clinically approved trimeric mRNA vaccine against RSV, but with greater durability. While intramuscular mRNA vaccines failed to induce effective respiratory mucosal immunity, the intranasal DNA nanocarrier-based vaccine achieved robust local and systemic immune activation, conferring potent protection against RSV infection. This rational design of intranasal RSV vaccines may be a general strategy for testing and advancing potent intranasal vaccines for a range of infectious respiratory diseases.

Nature Materials, 2026, https://doi.org/10.1038/s41563-026-02661-z