eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2025-12-30 18 4 2536 2550 10.13005/bpj/3275 69429 article Triana Hertiani 1 Kuntum Khaira Ummah 2 Titik Nuryastuti 3 Department of Pharmaceutical Biology, Gadjah Mada University, Yogyakarta, Indonesia Master of Pharmaceutical Science and Technology, Gadjah Mada University, Yogyakarta, Indonesia Department of Microbiology, Gadjah Mada University, Yogyakarta, Indonesia Diabetic foot ulcer (DFU) is a chronic complication of diabetes mellitus characterized by delayed healing and high recurrence rates. A key factor contributing to therapeutic failure is the presence of polymicrobial biofilms. Interspecies interactions within these biofilms promote EPS matrix thickening, antimicrobial resistance, immune evasion, and prolonged inflammation, thereby increasing the risk of amputation. This narrative review evaluates the clinical and therapeutic implications of these interactions and highlights strategies for effective management. A comprehensive search was conducted using Scopus, PubMed, and Google Scholar for studies published between 2015 and 2025. From 283 articles identified, 37 met the inclusion criteria and were reviewed. Results confirmed that interspecies interactions significantly impair wound healing and therapeutic outcomes in DFU. These interactions strengthen microbial persistence and delay tissue repair, underscoring the limited efficacy of conventional antimicrobial therapies. Clinically, debridement and negative pressure wound therapy (NPWT) remain the most widely supported interventions, while antibiotic–antibiofilm combinations and enzymatic EPS-disrupting agents show promising synergistic effects. Emerging modalities, including phage therapy, quorum sensing inhibitors, and smart dressings, are under development but largely restricted to preclinical studies. The clinical and therapeutic impact of interspecies interactions highlights the need for multimodal DFU management. Integrating mechanical and antibiofilm approaches with future innovations such as microbiota-guided personalized therapy and adaptive wound dressings may improve healing outcomes and reduce the risk of severe complications. https://biomedpharmajournal.org/vol18no4/polymicrobial-biofilms-in-diabetic-foot-ulcer-pathogenic-synergy-clinical-challenges-and-therapeutic-perspectives/ Antibiofilm therapy Diabetic foot ulcer Interspecies interaction Polymicrobial biofilm Quorum sensing Wound microbiota