The Role of Nanoparticle Surface Charge in the Generation of Mucosal and Systemic Antibody Responses Following Pulmonary Delivery

Nanoparticles have the potential to be excellent mucosal vaccine carriers, as they can diffuse through mucosa, associate with antigen presenting cells (APCs), and drain to regional lymph nodes, thus enhancing local humoral and cell-mediated mucosal protection. Varying nanoparticle properties, such as size, shape, and surface chemistry, can facilitate pathogen mimicry and co-delivery of relevant antigens and adjuvants.  However, optimal nanoparticle properties have not been identified for mucosal vaccine carriers.  Using the nano-molding technique Particle Replication In Non-wetting Templates (PRINT), we isolated the role of nanoparticle surface charge in two otherwise identical formulations of nanoparticles, which were covalently attached to a model antigen ovalbumin. Both formulations were readily internalized by lung APCs and drained to mediastinal lymph nodes.  However, cationic nanoparticles induced more potent APCs than anionic nanoparticles and upregulated co-stimulatory receptor molecules, cytokines, and chemokines. Pulmonary vaccination using cationic nanoparticles resulted in enhanced systemic and lung antibody titers, stemming from increased germinal center B-cell formation and CD4⁺ T-cell activation.  Our results indicate that nanoparticle surface charge is a main variable in driving T-cell dependent antibody responses in vivo and suggest the continued role of cationic nanoparticle platforms for engendering potent mucosal responses.