Inhalable Polymeric Nanoparticle Vaccine for Lysosome-targeting Co-delivery of Antigen and Adjuvant with Enhanced Immunoprotection

Abstract

Conventional subunit vaccines suffer from premature clearance and poor synchronization of antigen and adjuvant, limiting coordinated immune activation. Here, we develop an amphipathic polymer (YAXA) with acid-labile imine bonds for acid-sensitive degradation and terminal NHS-activated esters for antigen conjugation. YAXA is co-assembled with hydrophobic TLR7 agonist 3M-052 and conjugated to protein antigen, forming nanoparticle vaccine YM3.7. Following aerosolized intratracheal inoculation into the lung, YM3.7 is efficiently internalized by antigen-presenting cell and trafficked into lysosome, where acidic conditions trigger its dissociation and co-release of antigen and adjuvant. This spatiotemporally synchronized delivery promotes robust immune activation, including cell maturation, germinal center formation, systemic and lung-resident B/T cell response, and IgG/sIgA production. In lethal pneumonia models induced by either Pseudomonas aeruginosa or Staphylococcus aureus, YM3.7 markedly improves survival over conventional antigen and adjuvant mixture. This study presents an inhalable nanoparticle platform that coordinately activates innate, humoral, mucosal, and cellular immunity for enhanced protection.