Formulation strategies for bacteriophages targeting intracellular bacterial pathogens: A comprehensive review

Intracellular bacterial infections caused by pathogens such as Listeria monocytogenes , Salmonella enterica , and Mycobacterium tuberculosis represent a significant clinical challenge, particularly in the era of multidrug resistance (MDR). Bacteriophage (phage) therapy has re-emerged as a promising alternative therapeutic strategy; however, because phages have low intrinsic uptake into eukaryotic cells and poor access to intracellular bacteria, sophisticated formulations or engineering approaches are often needed to treat intracellular infections. This review systematically examines contemporary and emerging formulation strategies for increasing phage delivery to intracellular bacterial pathogens. Key approaches include encapsulation techniques using natural and synthetic polymers, nanocarrier-based delivery systems, genetic engineering modifications, and surface-functionalization strategies. We synthesized evidence from the literature spanning microbiology, nanomedicine, pharmaceutical sciences, and immunology to provide a comprehensive understanding of mechanistic pathways, comparative efficacy data, and challenges in clinical translation. Our analysis revealed that the most promising approaches combine multiple technologies, such as polymer blend encapsulation with nanocarrier systems and cell-penetrating peptides, to overcome physical, cellular, and immunological barriers. However, significant gaps remain in our knowledge of standardized evaluation protocols, long-term safety profiles, and subcellular trafficking mechanisms. This review identifies critical research priorities and proposes future directions for the advancement intracellular phage therapy in clinical practice.