Inhalable viromimetic polymer nanoparticle vaccine (iVPNVax) in a subcutaneous-prime/inhalation-boost vaccination schedule for eliciting durable mucosal and systemic immune protection.

Injectable vaccines seldom establish durable mucosal immunity in airways, permitting recurrent outbreaks of respiratory viruses. Although inhalation targets the respiratory mucosa directly, effective inhalable vaccines remain limited due to a size mismatch: pulmonary deposition favors micron-scale aerosols (∼1-5 μm), while mucosal penetration and antigen-presenting cell uptake require nanoscale carriers (<100 nm). In this study, we presented an inhalable viromimetic polymeric nanoparticle vaccine (iVPNVax) based on biocompatible PEG-b-PLA. Building on our previously established VPNVax platform, a microfluidic assembly was employed to reduce the particle size from ∼100 nm to ∼75 nm, thereby improving size uniformity and stability. During aerosolization, the iVPNVax nanoparticles were carried within micron-scale droplets that enabled efficient pulmonary deposition, after which they re-dispersed into nanoscale particles in the lung to support uptake by pulmonary cells. This delivery-driven pulmonary retention supported coordinated mucosal and systemic immunity, including robust BALF IgA production and the establishment of lung tissue-resident memory T (TRM) cells with a Th1/Th17 phenotype. In a SARS-CoV-2 Omicron BA.1 challenge, iVPNVax conferred superior protection compared with soluble antigen formulations. These findings reveal an inhalable nanoparticle vaccine platform that overcomes the key challenges associated with mucosal vaccination and provides a practical path for advancing respiratory vaccine development.