Phage therapy for mastitis in dairy cows: Multipathogen targeting strategies, clinical translation challenges, and...

Bovine mastitis is one of the most economically burdensome diseases in the global livestock industry. With the growing threat of antimicrobial resistance and the implementation of policies aimed at reducing or prohibiting antibiotic use, the development of novel antimicrobial strategies is urgently needed. Phage therapy, as a biological approach capable of precisely lysing pathogenic bacteria, holds promise as an alternative to antibiotics. This review systematically examines the scientific foundations of phage therapy, covering the phage life cycle, host recognition mechanisms, and the ability to degrade biofilms via depolymerases. It highlights the development strategies of phage cocktails, phage-based combination therapies, and preliminary evidence from preclinical models (e.g., mice) and limited bovine trials demonstrating the potential of phages in reducing bacterial load and alleviating inflammation. Key challenges are also discussed, including insufficient understanding of phage-host interactions within the complex mammary microenvironment, bottlenecks in phage preparation and formulation, the emergence of bacterial resistance, and the absence of a regulatory framework. Finally, this review outlines future research directions, emphasizing the potential of interdisciplinary strategies that integrate artificial intelligence-driven phage screening and rational design, nanomaterials, CRISPR-based gene editing, and novel delivery systems. By systematically summarizing concrete case studies and lessons learned from the clinical translation of phage therapy for bovine mastitis, with a particular focus on formulation engineering and delivery strategies applicable to livestock settings, this review provides a practical roadmap for advancing phage therapy from the laboratory to the farm.