Intranasal phage therapy overcomes antibody neutralization challenges in pulmonary Pseudomonas aeruginosa infections

Phage therapy is a promising approach against multidrug-resistant infections, yet systemic administration can lead to incomplete cures. We investigated the distribution, immune responses, and efficacy of the therapeutic phage KPP10 delivered via intranasal or intraperitoneal (IP) routes in murine Pseudomonas aeruginosa lung infection models. Intranasal pre-treatment achieved markedly higher localization of KPP10 in the lungs and bronchoalveolar compartment compared to IP delivery. Intranasal administration elicited minimal systemic antibody responses, whereas IP injection triggered significant IgG, IgM, and IgA production. Antibody responses did not differ significantly between doses. In acute and chronic infection models, intranasal KPP10 significantly improved survival (p < 0.01) and reduced lung bacterial loads relative to IP injection. Importantly, IP treatment was associated with bacterial rebound after day 14 in chronic infection, whereas intranasal dosing sustained bacterial clearance. These findings demonstrate that intranasal delivery enhances pulmonary localization, minimizes antibody-mediated neutralization, and provides superior therapeutic efficacy, highlighting its potential as a more effective route for phage therapy against P. aeruginosa lung infections.