Development of a chitosan-based acid-responsive mucoadhesive mRNA vaccine for eliciting mucosal and systemic immunity.

Mucosal mRNA vaccines are promising for establishing immune barriers at pathogen entry points to prevent its infection and transmission. Nevertheless, these vaccines encounter challenges including rapid clearance, low reactivity to antigens, and suboptimal mRNA transfection efficiency. Addressing these limitations, we engineered an acid-responsive mRNA vaccine (PQOm) based on the Schiff-base polymers composed of quaternized chitosan (QCS), low molecular weight polyethyleneimine, and aldehyde functionalized polyethylene glycol, to stimulate potent mucosal and systemic immune responses. During the construction of PQOm, we not only revealed the significant impact of steric hindrance on mRNA transfection efficiency, but also demonstrated its ability to realize acid-responsive mRNA release and efficient mRNA transfection. Owing to the synergistic effect of its components, PQOm provided continuous stimulation to the nasal-associated lymphoid tissue (NALT) by adhering to the nasal mucosa for extended periods of up to 6 days. The continuous NALT stimulation, efficient transfection, and adjuvant effect of QCS collectively allowed PQOm to address the low reactivity of NALT to antigen, triggering robust mucosal and systemic immune responses without significant toxicity. In conclusion, PQOm represents a promising mucosal mRNA vaccine with high clinical potential for preventing viral infections.