Targeting the Pathological Microenvironment in Diabetic Foot Ulcers: Advances in Drug Delivery Systems for Improved Healing.

ABSTRACT Diabetic foot ulcers (DFUs) are among the most severe and disabling complications of diabetes, characterized by delayed healing, frequent recurrence, and a high risk of infection and amputation. Their pathogenesis is sustained by a hostile pathological microenvironment involving persistent inflammation, oxidative stress, protease imbalance, impaired angiogenesis, and immune dysregulation, while systemic factors such as metabolic disturbance and gut‐skin axis dysfunction may further aggravate non‐healing. Although conventional management remains essential, it often has limited ability to directly correct these underlying drivers. In response, recent advances in formulation technologies have increasingly focused on mechanism‐guided intervention in the wound microenvironment. These include nanocarriers and scaffold platforms for local delivery, stimuli‐responsive and photoactivatable nanomedicine, functional biomaterials, cell‐free regenerative systems, and gut‐directed adjunctive strategies. Together, these approaches aim to improve local retention, enable on‐demand therapeutic activation, actively remodel the pathological microenvironment, and reduce extra‐wound inflammatory and metabolic burdens. This review summarizes recent progress in microenvironment‐targeted DFUs therapies and highlights the potential of more precise and mechanism‐guided treatment strategies tailored to the biological heterogeneity of wounds.