A facile microfluidics based polysaccharide-functionalized virus-mimicking nanovaccine for circumventing pulmonary innate physiological barriers and augmenting immunity.

The escalating prevalence of COVID-19 variants and influenza has garnered substantial attention to lung vaccines lately. Nevertheless, the intrinsic immune barriers present within the lung significantly tend to compromise the efficacy of nanovaccines. Moreover, the deficiency of safe and efficacious inhalable adjuvants also impedes the advancement of nanovaccines. Herein, we devised polysaccharide-functionalized virus-mimicking nanovaccines via a facile microfluidics approach, wherein chitosan-based polyelectrolyte complexes serve as the inner core (CS-OVA), and heparan sulfate (SH) modification further emulates the structure and composition of the viral exterior. Compared to CS-OVA, SH/CS-OVA revealed remarkable efficacy in surmounting pulmonary physiological barriers, demonstrating a 3-fold enhancement in traversing the mucus lining and a 4.8-fold increase in evading macrophage engulfment. It has also been substantiated to exhibit exceptional in vivo dendritic cell (DC) recruitment and uptake, accompanied by enhanced DC maturation capabilities over CS-OVA. Furthermore, in vivo imaging uncovered significantly prolonged lung retention and rapid lymph nodes drainage. Notably, SH/CS-OVA elicited elevated levels of specific serum IgG and isotype titers, initiating potent T cell and triple immune responses, along with the robust T cell immune memory upon intrapulmonary administration. In summary, the polysaccharide-functionalized virus-mimicking nanovaccine (SH/CS-OVA) presents a safe and effective nanotherapeutics platform for inhaled immunotherapy.