Spiky mesoporous silica-based nanovaccines enhance mucosal immunity with improved intestinal retention and antigen accessibility.

Intestinal vaccination faces several key challenges, including limited epithelial interaction, inefficient antigen uptake, and insufficient immune stimulation. Here, we developed a virus-inspired oral nanovaccine based on spiky mesoporous silica nanoparticles (VMSNs) functionalized with Rehmannia glutinosa polysaccharide (RGP), a natural polysaccharide with favorable intestinal biocompatibility. The resulting RGP-VMSN showed enhanced intestinal retention and epithelial interaction and was associated with increased antigen accessibility within the mucosal environment, reflected by stronger antigen-associated signals at mucosal immune sites. Using ovalbumin (OVA) as a model antigen, oral OVA@RGP-VMSN vaccination was associated with increased intestinal dendritic cell activation, enhanced germinal center responses, and elevated antigen-specific antibody production, together with coordinated mucosal and systemic immune responses. Furthermore, immunization with a Salmonella enterica serovar Typhimurium lysate-loaded nanovaccine improved protection in a murine challenge model. Overall, this strategy represents a promising platform for oral and mucosal nanovaccine development.