Cytosol‐Targeting Delivery of Non‐Nucleotide STING Agonist Achieves Inhalable Nanoparticle‐Based Anthrax Vaccine

Inhalational anthrax is a deadly disease caused by inhalation of Bacillus anthracis spores. Current anthrax vaccines for human use have limitations including undefined components, limited mucosal immunity, and suboptimal adjuvant delivery. This study introduces 2 polymers, MP1 and MP2, each containing disulfide bonds. MP1 incorporates tertiary amines to induce proton sponge effect, while MP2 features terminal phenylboronic acid moieties for protein conjugation. Nanoparticle vaccine YM1.7 is created through self-assembly of MP1, MP2, and STING agonist MSA-2, followed by N─B coordination of recombinant protein antigen (rPA) on its surface. When administered via aerosolized intratracheal inoculation into the lung, YM1.7 is internalized by antigen-presenting cell and trafficked to the lysosome, where acidic environment dissociates N─B bond, releasing rPA for antigen presentation. Proton sponge effect allows nanoparticle to escape into the cytosol, and then disulfide bond cleavage triggered by cytosolic glutathione causes dissociation of nanoparticle and release of MSA-2 within the cytosol, significantly enhancing bioavailability of MSA-2 as an adjuvant. This spatiotemporal delivery mechanism elicits a coordinated innate, humoral, mucosal, and cell-mediated immune response in mice, providing strong protection against inhalational anthrax. Given its modular design nature, YM1.7 represents a promising platform for developing next-generation mucosal vaccines against infections and cancers.