Multi-Kingdom Biofilms Breached: Microneedle Delivery of Metabolically Targeted Organic Silver–Photosensitizers for Polymicrobial Infections in Diabetic Foot Ulcers

Abstract

Abstract Chronic diabetic foot ulcers (DFUs) provide a favorable niche for microbial colonization, where complex polymicrobial infections involving Gram-positive bacteria, Gram-negative bacteria, and fungi frequently occur and severely impair wound healing through biofilm formation. Photodynamic therapy (PDT) offers a broad-spectrum and resistance-independent antimicrobial strategy; however, its efficacy is often limited by insufficient photosensitizer accumulation and poor penetration into mature polymicrobial biofilms. Herein, a series of triphenylamine-based organic silver photosensitizers (T-C12-Ag, T-BOB-Ag, and T-DAla-Ag) incorporating distinct targeting motifs, including hydrophobic interaction, glycan recognition, and bacterial metabolic labeling, is rationally designed to address the complexity of diabetic foot infections. Comparative evaluation in a representative polymicrobial infection model composed of Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans demonstrates that the D-amino-acid–functionalized probe (T-DAla-Ag) achieves the most efficient microbial labeling and penetration within mixed bacterial–fungal biofilms. Integration of T-DAla-Ag into a dissolvable microneedle platform enables rapid drug release into deep biofilm layers. Upon light activation, synergistic reactive oxygen species generation and Ag⁺ release result in potent antimicrobial activity, leading to reduced pathogen burden, alleviated inflammation, and accelerated wound healing in diabetic infection models. This work establishes an effective strategy for managing complex biofilm-associated infections in diabetic wounds.