DAT@Zr-MOF nanocomposite hydrogel accelerates skin wound healing by remodeling the immune-vascular microenvironment.

Skin wound healing remains a prominent clinical challenge, creating an urgent demand for high-performance wound-care biomaterials. Deaminotyrosine (DAT), a recently identified flavonoid-derived gut metabolite, exhibits anti-inflammatory and immunomodulatory activities. Nevertheless, its translational application is greatly restricted by poor aqueous solubility, insufficient stability, and potential dose-dependent toxicity. Herein, we fabricated a novel zirconium-based metal-organic framework carrier loaded with DAT (denoted DAT@Zr-MOF). The resulting nanocomposite displayed a uniform spherical morphology, favorable colloidal stability, and satisfactory drug loading capacity. In vitro experiments verified its desirable hemocompatibility and cytocompatibility. DAT@Zr-MOF could be efficiently internalized by HUVECs and markedly facilitate endothelial angiogenesis, proliferation, and migration. Additionally, it inhibited LPS-triggered NF-κB signaling activation, TNF-α secretion, and ROS accumulation in RAW264.7 macrophages. After integration into a thermosensitive poloxamer 407 hydrogel, DAT@Zr-MOF significantly accelerated wound closure in a murine full-thickness skin defect model. The formulation facilitated re-epithelialization, collagen deposition, and neovascularization, achieving superior therapeutic effects relative to the blank control and free DAT groups. RNA-seq profiling of day-15 wound tissues identified 549 differentially expressed genes (DEGs). Functional enrichment analyses indicated that these DEGs were closely associated with core biological events, including skin development, keratinocyte differentiation, cytokine-receptor interactions, and leukocyte migration. Protein-protein interaction network analysis further uncovered hub genes such as Krt84, Ccl19, and Csf2. Collectively, the DAT@Zr-MOF composite hydrogel expedites cutaneous wound healing by synergistically modulating angiogenesis, inflammatory response and tissue remodeling through multi-pathway transcriptional regulation. This study offers a promising strategy for the design of advanced wound dressings.