SARS-CoV-2
is a respiratory virus that causes significant threats
to human health. Mucosal immunity provides a first-line defense to
prevent the infection of SARS-CoV-2 in the respiratory tract. Because
most SARS-CoV-2 vaccines could not stimulate mucosal immunity in the
respiratory tract, appropriate mucosal adjuvants or delivery systems
are needed for mucosal vaccine development. Mannan, polyarginine,
and 2′,3′-cGAMP are three mucosal adjuvants that could
stimulate mucosal immunity. In the present study, the three adjuvants
were assembled with a receptor-binding domain (RBD) by electrostatic
interaction to generate a nanoparticle vaccine (RBD-MP-cG). RBD-MP-cG
elicited mucosal IgA and IgG response in bronchoalveolar lavage and
nasal lavage by intranasal administration. It induced a robust RBD-specific
antibody response, high levels of protective neutralizing antibody,
and ACE2-blocking activity in the mouse sera. It stimulated the splenic
secretion of high levels of Th1-, Th2-, and Th17-type cytokines. Thus,
RBD-MP-cG elicited strong mucosal immunity and systematic immunity
by intranasal administration. RBD-MP-cG was expected to act as a safe,
effective, and easily produced mucosal nanoparticle vaccine to combat
the infection of SARS-CoV-2.