Diabetic foot osteomyelitis: pathological microenvironment and matching tailored treatment strategies

Diabetic foot osteomyelitis (DFO) often manifests as persistent, non-healing infection with progressive bone destruction. Poor glycemic control and concomitant peripheral vascular and neuropathic injury are key drivers. Effective clinical solutions remain limited. Current management typically involves debridement of infected and necrotic tissues, local or systemic antibiotics, and bone/soft-tissue reconstruction. However, impaired local circulation makes it difficult to sustain therapeutic antibiotic levels at the lesion site. Recurrence is therefore common. Bone regeneration is also hard to achieve, which prolongs the overall course and results in repeated procedures, long recovery cycles, and high costs. To overcome these limitations, we propose a microenvironment-matched strategy as a practical direction for DFO therapy. The DFO niche is characterized by bacterial persistence and recurrent infection, severe oxidative stress and chronic inflammation, immunometabolic dysregulation, and microvascular plus neural injury that suppress osteogenesis. These constraints converge on three intertwined therapeutic targets: infection, inflammation, and bone defects. Treatment should thus be precise, sequential, and coordinated across targets, rather than relying on isolated interventions. This review systematically summarizes advances in multitarget antibacterial approaches, anti-inflammatory and immunometabolic modulation, and multifunctional biomaterial platforms that integrate angiogenesis, neurorestoration, and osteogenic regeneration. We further highlight microenvironment-responsive, integrated strategies that optimize drug dosing and release timing, aiming to improve the durability of infection control and the quality of bone reconstruction. Ultimately, we provide researchers with testable material design and synthesis logic, and offer clinicians new therapeutic paradigms and stage-adaptive, precision care pathways.