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Overexpression of matrix metalloproteinase\u20109 (MMP\u20109) and the consequent MMP\u20109\/TIMP1 (tissue inhibitor of metalloproteinase 1) imbalance delays healing by degrading the extracellular matrix, impairing granulation tissue formation, and exacerbating inflammation. Conventional therapies do not dynamically respond to fluctuating protease levels in chronic wounds. This study introduces an MMP\u20109\u2010responsive protein release system (M9RR), where the therapeutic protein (i.e., TIMP1) is linked to a membrane\u2010anchoring domain at its C\u2010terminus via an MMP\u20109\u2010cleavable peptide, thereby exposing the fusion protein to the extracellular side of cell membranes. The system enables targeted release of TIMP1 in high\u2010MMP\u20109 microenvironments, thereby neutralizing excessive MMP\u20109 activity. In vitro, M9RR demonstrates MMP\u20109 specificity, broad mammalian cell applicability, and protection of HaCaT keratinocytes and BJ fibroblasts from MMP\u20109\u2010induced damage. In db\/db diabetic mice, the MMP\u20109\u2010responsive TIMP1 release system (TIMP1\n                    <jats:sup>M9RR<\/jats:sup>\n                    ) significantly improves wound contraction, granulation tissue formation, epithelial regeneration, and collagen remodeling. Additionally, a cryomicroneedle (CryoMNs)\u2010based co\u2010delivery system for basic fibroblast growth factor (bFGF) and TIMP1\n                    <jats:sup>M9RR<\/jats:sup>\n                    shows effective diabetic wound healing. This modular M9RR system offers a precise, adaptive therapeutic strategy for DFU and holds promise for other MMP\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202524328","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Situ Genetic Engineering Facilitates MMP\u20109\u2010Responsive TIMP1 Release Through Proteolytic Cleavage to Boost Diabetic Wound Healing"],"prefix":"10.1002","author":[{"given":"Yuan","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences Faculty of Medicine Key Laboratory for Regenerative Medicine, Ministry of Education of China The Chinese University of Hong Kong  Hong Kong People's Republic of China"},{"name":"National Infrastructures for Translational Medicine (Peking Union), Peking Union Medical College 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