Hydrogel as Drug Delivery Systems for Bacteriophage Therapy: Overcoming Biological Barriers in Multidrug Resistant...

The rapid emergence of multidrug-resistant (MDR) bacterial infections has intensified the demand for advanced antimicrobial drug delivery strategies capable of improving therapeutic efficacy while overcoming the limitations of conventional antibiotics. Bacteriophage therapy has re-emerged as a promising antibacterial approach because of its high specificity and potent activity against antibiotic-resistant pathogens. Nevertheless, the clinical translation of free bacteriophages remains restricted by multiple biological barriers, including rapid immune clearance, limited retention at infection sites, enzymatic degradation, poor stability, and inadequate penetration into bacterial biofilms. Hydrogel-based drug delivery systems have emerged as versatile biomaterial platforms that effectively address these challenges by protecting bacteriophages from environmental degradation, enabling localized administration, prolonging residence time, and providing sustained and controlled phage release. This review critically discusses the major biological barriers limiting successful bacteriophage therapy and highlights recent advances in hydrogel engineering strategies designed to improve phage encapsulation, stability, release behavior, and antibacterial efficacy. Furthermore, the physicochemical characteristics of hydrogels that influence phage delivery, including biocompatibility, porosity, swelling behavior, degradability, tissue adhesiveness, and mechanical properties, are examined in relation to their effects on phage retention and release. Recent applications of hydrogel-assisted bacteriophage delivery in chronic wound infections, biofilm-associated infections, surgical site infections, and other MDR bacterial diseases are summarized, with particular emphasis on localized antimicrobial therapy. Finally, current challenges related to formulation design, large-scale manufacturing, regulatory approval, and clinical translation are discussed, together with future perspectives for developing clinically applicable hydrogel-based phage delivery systems. Collectively, this review evaluates the current evidence supporting hydrogel-mediated bacteriophage delivery and identifies key considerations for the development and clinical translation of effective localized phage delivery systems against multidrug-resistant bacterial infections.