From Antagonism to Coevolutionary Regulation: Multidimensional Phage–Biofilm Interaction Networks and Translational Targeted Anti-Infection Strategies

Bacterial biofilms possess inherent physical barriers and structural heterogeneity. These features pose a major obstacle to clinical anti-infective therapy. This review systematically examines the dynamic interplay between phages and bacterial biofilms, which ranges from antagonistic competition to synergistic interaction. It aims to dissect the underlying mechanisms and translational potential of phages as next-generation precision anti-infective agents. A core scientific question in phage–biofilm interactions is how phages penetrate and remodel the three-dimensional extracellular matrix of biofilms. Classic mechanisms include direct lysis of bacteria embedded in biofilms, degradation of matrix scaffolds by phage-derived exopolysaccharide depolymerases, and modulation of bacterial virulence and biofilm phenotypes via lysogenic conversion. Auxiliary mechanisms encompass synergistic bactericidal effects of phages and the host’s innate immune system, as well as niche competition within microbial communities. Recently identified mechanisms involve phage-mediated interference with bacterial quorum sensing, physical remodeling of biofilm spatial architecture, and enhanced antibiotic penetration across biofilm barriers. These processes collectively shape the microenvironmental network linking phages, bacteria, and host cells. By synthesizing the complex phage–biofilm interplay, this review provides a theoretical basis for designing engineered phage cocktails, optimizing phage–antibiotic combination regimens, and developing intelligent biomaterial delivery systems. These delivery systems are intended for targeted treatment of chronic biofilm-associated infections.