Abstract

Abstract Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan–catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS‐CoV‐2 spike protein receptor‐binding domain (RBD) and toll‐like receptor (TLR)9 agonist unmethylated cytosine‐guanine (CpG) motif, forming uniform virus‐like nanoparticles (Ssp‐Chic‐RBD‐CpG) via electrostatic and covalent interactions. Ssp‐Chic‐RBD‐CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92‐fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C‐C motif) ligand 20 (CCL20)‐driven DCs recruitment and maturation by Ssp‐Chic‐RBD‐CpG are evidenced by a cell co‐culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF‐κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein‐based subunit vaccines as well when intranasal administration is needed.