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.