Hydrogel as a drug delivery systems for bacteriophage therapy: overcoming biological barriers in multidrug-resistant bacterial infections

The emergence of multidrug resistant (MDR) bacterial infections has intensified the need for effective antimicrobial strategies beyond conventional antibiotics. Bacteriophage therapy offers a promising approach against antibiotic resistant pathogens; however, its clinical translation is limited by immune clearance, enzymatic degradation, poor stability, insufficient retention at infection sites, and limited penetration into bacterial biofilms. Hydrogel based delivery systems provide versatile biomaterial platforms to overcome these barriers by protecting bacteriophages, enabling localized administration, prolonging residence time, and controlling phage release. This review critically examines the biological barriers limiting bacteriophage therapy and recent advances in hydrogel engineering to improve phage encapsulation, stability, release behavior, and antibacterial efficacy. Key hydrogel properties, including biocompatibility, porosity, swelling, degradability, tissue adhesiveness, and mechanical strength, are discussed in relation to phage retention and delivery performance. Recent applications in chronic wound infections, biofilm associated infections, surgical site infections, and other MDR bacterial diseases are evaluated, with emphasis on localized antimicrobial treatment. Furthermore, challenges in formulation development, large scale manufacturing, regulatory approval, and clinical translation are explored. By integrating current evidence on hydrogel design, phage delivery, and therapeutic performance, this review identifies critical considerations for developing effective and clinically applicable hydrogel based bacteriophage delivery systems against MDR bacterial infections.