Biofilm-Host Immune Crosstalk at the Diabetic Foot Ulcer Interface: Molecular Mechanisms, Immune Evasion, and Next-Generation Anti-Biofilm Strategies.

Diabetic foot ulcers (DFUs) are chronic wounds in which microbial persistence and defective host defense interact to impair healing. This review examines DFU through the biofilm-host immune interface rather than viewing biofilm as a purely microbiological problem. We summarize how the diabetic wound milieu, including hyperglycemia, impaired perfusion, neuropathy, and polymicrobial community structure, favors persistent biofilm infection, and how DFU-relevant biofilms evade clearance through matrix shielding, altered innate recognition, virulence-associated host modulation, and intracellular Staphylococcus aureus persistence. We further highlight two major immune-dysregulation axes: excessive neutrophil extracellular trap formation with NLRP3-centered inflammatory amplification, and perforin-2 suppression linked to AIM2-mediated pyroptotic injury. We also appraise emerging immune-aware antibiofilm strategies, particularly quorum-sensing interference, enzymatic matrix disruption, phage therapy, and selected immune-directed interventions. Overall, current evidence supports a model in which non-healing DFU reflects failed host-pathogen resolution at the biofilm-immune interface, with important implications for mechanism-guided therapeutic development.