Beyond Antibacterial Activity: Engineering Multifunctional Biomaterials for Multidrug-Resistant Infections

Antimicrobial resistance is increasingly limiting the effectiveness of conventional antibiotic therapy, particularly in chronic wounds, biofilm-associated infections, and implant-related infections. Antimicrobial biomaterials have emerged as promising alternatives; however, much of the field remains organized around material classes or pathogen killing alone, with comparatively limited consideration of the complex biological environment in which infection develops and persists. This review proposes a function-based framework in which antimicrobial biomaterials are designed as integrated therapeutic systems rather than as passive antimicrobial carriers. Six complementary engineering functions are identified: infection targeting, overcoming bacterial defenses, multimodal pathogen eradication, host immune modulation, tissue regeneration, and adaptive or stimuli-responsive behavior. For each function, key design principles, representative strategies, and translational challenges are critically examined. Particular attention is given to the extent to which these functions have been experimentally integrated, including a systematic assessment of demonstrated versus largely conceptual pairwise combinations. Because the relative importance of each function varies by clinical application, the review also considers how these priorities shift across tissue and device context, including skin and soft tissue, bone, and short-term devices such as indwelling catheters. Rather than emphasizing efficacy alone, the review also examines translational limitations and failure points, including inadequate activity against clinically relevant organisms, limited clinical validation of established antimicrobial technologies, and regulatory failure of promising antimicrobial candidates. These examples highlight the persistent gap between laboratory performance and clinical utility. The review further considers the emerging tension between broad-spectrum antimicrobial strategies and approaches designed to preserve the host microbiome through species-selective targeting. Special emphasis is placed on halogen-based antimicrobial systems, catalytic nanozymes, and the emerging application of artificial intelligence to biomaterial design. Finally, a prioritized roadmap is proposed for advancing multifunctional antimicrobial biomaterials from mechanistic proof-of-concept toward clinically relevant therapeutic systems, while identifying key assumptions and knowledge gaps that remain to be validated.