Strategies to Enhance the Efficacy and Clinical Translation of Antimicrobial Photodynamic Therapy

Background: Antimicrobial resistance represents a growing global health challenge, necessitating the development of effective non-antibiotic antimicrobial approaches. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising localized antimicrobial strategy owing to its broad-spectrum activity, biofilm-targeting capability, and low propensity to induce resistance. However, its clinical translation remains restricted by limited photosensitizer (PS) performance, insufficient light penetration, oxygen dependency, biofilm-associated barriers, and the lack of standardized treatment protocols. Methods: This narrative review summarizes recent strategies developed to enhance the efficacy and translational potential of aPDT, including PS engineering, nanomaterial- and non-nanomaterial-based delivery systems, advanced light-source technologies, hypoxia-modulating approaches, and synergistic therapeutic strategies. In addition, current challenges associated with regulatory approval, manufacturing scalability, treatment standardization, and clinical implementation are discussed. Results: Recent advances have transformed aPDT from a conventional PS-light-oxygen system into a multifunctional antimicrobial platform. Emerging approaches improve bacterial targeting, biofilm penetration, reactive oxygen species generation, oxygen utilization, and therapeutic precision. Nevertheless, many advanced systems remain at the preclinical stage due to complexity, cost, safety concerns, and insufficient clinical validation. Conclusions: aPDT should be considered a targeted therapeutic option for accessible, localized, and biofilm-associated infections rather than a replacement for systemic antimicrobial therapy. Future clinical translation will depend on balancing technological innovation with biosafety, scalability, and protocol standardization. Strategies integrating intelligent PS design, oxygen regulation, and clinically feasible synergistic approaches may provide promising pathways toward the broader application of aPDT in antimicrobial management.