Inhalable Polymeric Nanoparticle Vaccine for Lysosome‐Targeting Co‐Delivery of Antigen and Adjuvant With Enhanced Immunoprotection

Conventional subunit vaccines, typically formulated as a simple antigen and adjuvant mixture, suffer from premature clearance and poor synchronization of antigen and adjuvant, resulting in suboptimal immune activation. Here, we develop an amphipathic polymer, YAXA, featuring acid-labile imine bonds for pH-responsive degradation and terminal NHS-activated esters for covalent conjugation of protective antigen. Through hydrophilic-hydrophobic co-assembly with the hydrophobic TLR7 agonist 3M-052, followed by antigen conjugation, YAXA forms an inhalable nanoparticle vaccine, YM3.7, in which the antigen is displayed on the hydrophilic surface while the adjuvant is encapsulated in the hydrophobic core. Following aerosolized intratracheal inoculation into the lung, YM3.7 is efficiently internalized by antigen-presenting cells and trafficked into the lysosome, where acidic conditions trigger its dissociation and co-release of antigen and adjuvant. This lysosome-targeted, spatiotemporally synchronized delivery couples antigen presentation with TLR7/NF-κB activation, driving robust immune responses, including antigen-presenting cell maturation, germinal center formation, systemic and lung-resident B/T cell response, and IgG/sIgA production. In lethal pneumonia models induced by Pseudomonas aeruginosa or Staphylococcus aureus, YM3.7 markedly improves survival over a conventional antigen and adjuvant mixture. This research establishes a paradigm for developing next-generation inhalable nanoparticle vaccines, capable of spatiotemporally coordinating innate immunity, humoral immunity, mucosal immunity, and cell-mediated immunity to provide enhanced immunoprotection.