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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\u2010skin axis dysfunction may further aggravate non\u2010healing. 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\u2010guided intervention in the wound microenvironment. These include nanocarriers and scaffold platforms for local delivery, stimuli\u2010responsive and photoactivatable nanomedicine, functional biomaterials, cell\u2010free regenerative systems, and gut\u2010directed adjunctive strategies. Together, these approaches aim to improve local retention, enable on\u2010demand therapeutic activation, actively remodel the pathological microenvironment, and reduce extra\u2010wound inflammatory and metabolic burdens. This review summarizes recent progress in microenvironment\u2010targeted DFUs therapies and highlights the potential of more precise and mechanism\u2010guided treatment strategies tailored to the biological heterogeneity of wounds.<\/jats:p>","DOI":"10.1002\/jbm.b.70079","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T06:31:45Z","timestamp":1776666705000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting the Pathological Microenvironment in Diabetic Foot Ulcers: Advances in Drug Delivery Systems for Improved Healing"],"prefix":"10.1002","volume":"114","author":[{"given":"Wanqing","family":"Dai","sequence":"first","affiliation":[{"name":"School of Pharmacy Anhui University of Chinese Medicine  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengguang","family":"Li","sequence":"additional","affiliation":[{"name":"Taihe County People's 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