Rapid and potent induction of protective mucosal immunity against SARS-CoV-2 by an adenovirus-vectored nanoparticle vaccine.

Effective vaccine design ideally elicits potent, durable, and broad-spectrum immunity against rapidly evolving pathogens. However, current platforms, such as recombinant adenovirus vectors and protein nanoparticles, are developed and administered separately, and each has distinct immunological and practical limitations. Here, we introduce a synergistic vaccine framework that intrinsically combines genetic delivery with rational antigen design. We engineer an adenovirus type 5 vector to co-express a prefusion-stabilized SARS-CoV-2 spike and ferritin subunit (Ad5-SpFN), which drives in vivo assembly of spike-decorated nanoparticles. Compared to either platform alone, this unified strategy elicits faster and higher neutralizing antibody titers and robust T-cell responses, and confers complete protection against lethal viral challenge. Mechanistically, Ad5-SpFN enhances early dendritic cell activation and germinal center reactions, leading to a more potent and sustained humoral immune response. Furthermore, it provides exceptional route flexibility, establishing protective mucosal immunity after intranasal administration, which addresses a key limitation of many existing vaccines. This versatile "vector-nanoparticle" hybrid platform can be rapidly reprogrammed, offering a promising strategy for future pandemic preparedness.