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Pseudomonas aeruginosa is an emergent threat due to the antimicrobial resistance crisis. Bacteriophages (phages) are promising agents for phage therapy approaches against P. aeruginosa. It has been proposed that metazoans harbor phages on their mucosal surfaces, and this could be exploited for the rational design of prophylactic phage therapy. The goal of this study was to evaluate the potential of phage-mucus interaction to prevent infections caused by P. aeruginosa. We isolated two phages capable of infecting P. aeruginosa. Both are similar in morphology and closely related genetically. However, phage VAC3 is more efficient in replicating in mucin-exposed P. aeruginosa in vitro and is preferentially held in the respiratory tract of C57BL/6 mice. Pre-treatment with VAC3 phage protects mice from a lethal dose of P. aeruginosa while VAC1 does not. This shows that phages adapted to mucosal conditions have potential to be applied as prophylactic measures against an ESKAPE pathogen., Competing Interests: Competing interests: We declare that G.M.F.A. is one of the owners of a patent titled “Improved methods and culture media for production, quantification and isolation of bacteriophages” (FI20185086, PCT/FI2019/050073). All the other authors have no competing interests as defined by Nature Portfolio, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Ethics statement: The Institutional Animal Care and Use Committee approved all animal experimental protocols (0041/2021) of the Federal University of Alfenas (Minas Gerais, Brazil). We have complied with all relevant ethical regulations for animal use. All eight-week-old female Mus musculus C57BL/6 mice used in this study were maintained with free access to food and water according to the local animal welfare regulations (protocol 0041/2021)., (© 2025. The Author(s).)