Intelligent-responsive hydrogel synergistically mediates immune remodel-antibacterial-angiogenesis cascade for diabetic foot ulcer repair

The healing of diabetic foot ulcers (DFU) is severely hindered by dysregulated immune microenvironment, recurrent infections, and insufficient angiogenesis. The persistent and resistant nature, coupled with elevated morbidity and amputation rates, has driven the scientific community to pursue the development of novel therapies. Current wound dressings mostly target a singular aspect and fail to achieve systematic regulation of these dynamically related factors, highlighting the urgent need for dressings capable of accurate sense and response to the complex pathological process of wound and precise repair. Herein, an intelligent treatment strategy of "intelligent response - synergistic regulation" was proposed. We designed a desferrioxamine-loaded Mn-doped zeolitic imidazolate framework-8 (DFO@Mn-ZIF-8), which exhibits dual enzyme-mimetic activity to scavenge excess reactive oxygen species (ROS) and, upon disintegration, combats infection and promotes angiogenesis. Subsequently, a glucose- and ROS-responsive chitosan-based hydrogel loaded with DFO@Mn-ZIF-8 and umbilical cord mesenchymal stem cell-derived exosome was fabricated (Exo/MOF@CPH). In a validated S. aureus -infected diabetic wound model, Exo/MOF@CPH continuously senses and responds to the dynamic wound microenvironment, simultaneously achieving bacterial clearance, immune reconstitution, and angiogenesis promotion, thereby fostering a healing-friendly microenvironment. This multifunctional single-platform therapy offers a promising translational strategy for DFU repair, advancing smart biomaterial design for complex pathological microenvironment. • A novel multifunctional platform (Exo/MOF@CPH) is developed for intervening multiple critical pathological processes of DFU. • Exo/MOF@CPH synergistically regulates macrophage polarization to remodel immune, clears bacteria, and promotes angiogenesis. • The hydrogel accelerates healing via HIF-1α-VEGF, PI3K-Akt, and JAK-STAT pathways, enhancing robust tissue regeneration.