These are important milestones in the development of an intracellular bacteriophage therapy that might be useful in the fight against multi-drug-resistant intracellular pathogens like Mycobacterium tuberculosis.

More and more bacteria are developing severe antibiotic resistance. Among them are important intracellular pathogens such as Mycobacterium tuberculosis. Alternatives to classical antibiotics are urgently needed and bacteriophage therapy is a promising candidate for alternative or supplemental treatment. Until now, bacteriophages have been thought to be non-suitable for therapy against intracellular pathogens. Still, a few studies have been carried out to assess the efficacy of bacteriophage therapy against intracellular pathogens both in vitro and in vivo, with variable results. Recently, some successful studies have been conducted, in which bacteriophages were carried into infected cells by different bacterial vectors and killed intracellular pathogens. In this review, we aim to recapitulate the existing literature on bacteriophage therapy of intracellular pathogens and discuss possible ways of bacteriophage entry into infected cells, including different Trojan horse strategies and the question of whether free bacteriophages are able to enter mammalian cells. Finally, we sum up attempts of bacteriophage microencapsulation and speculate about the advantages of artificial vectorization for efficient and targeted intracellular delivery.

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