Engineering phage therapeutics with intrinsic biocontainment

Engineered bacteriophages (phages) are emerging as a promising next generation of antibacterial phage therapeutics, facilitated by advances in synthetic biology, genome engineering, and computational design. Engineered phage therapeutics offer standardised genome designs, expanded functionality, and improved manufacturability, which could potentially help to overcome regulatory barriers. However, genetically engineered phages raise additional biosafety and environmental concerns, making the development of effective biocontainment strategies important for clinical use. Here, we review current approaches for phage genome engineering, alongside the evolving regulatory frameworks for engineered phages. We evaluate emerging biocontainment strategies for therapeutic phages and propose a framework for assessing trade-offs between biocontainment stringency, evolutionary robustness against escape mutants, therapeutic efficacy, and translational feasibility.