A dual-crosslinked silk fibroin hydrogel with aldehyde-functionalized glycyrrhizic acid as a structural-pharmacological crosslinker for diabetic wound healing.

Diabetic wounds are characterized by persistent oxidative stress, dysregulate inflammation, impaired angiogenesis, and defective tissue repair. Developing wound dressings that simultaneously provide mechanical adaptability and active modulation of the pathological microenvironment remains challenging. Here, we developed a dual-crosslinked silk fibroin-based hydrogel (SCG) composed of methacrylated silk fibroin (SFGMA), oxidized carboxymethyl cellulose (OCMC), and aldehyde-functionalized glycyrrhizic acid (AGA). SFGMA formed a photocrosslinked covalent network, whereas OCMC and AGA introduced dynamic Schiff-base interactions with silk fibroin amines. Notably, AGA served as a structural-bioactive component by participating in network formation while retaining glycyrrhizic-acid-associated antioxidant and immunomodulatory activity. The SCG precursor exhibited syringe deliverability and rapid in situ photocuring, while the resulting hydrogel showed dynamic self-recovery, enhanced mechanical stability, interconnected porosity, controlled swelling and degradation, and good cyto- and hemocompatibility. In vitro, AGA-containing hydrogels markedly reduced reactive oxygen species and favored an M2-like macrophage phenotype, characterized by increased CD206, Arg-1, IL-10, and TGF-β expression together with reduced CD86, iNOS, and IL-6 expression. In LPS-stimulated macrophages, AGA-containing formulations also decreased extracellular HMGB1 levels. SCG further enhanced endothelial migration and tube formation. In a streptozotocin-induced diabetic full-thickness wound model, SCG promoted early wound-area reduction and significantly improved histological re-epithelialization, collagen matrix deposition, and vascularization, accompanied by reduced inflammatory-marker expression and increased M2-associated tissue markers. Collectively, these findings identify AGA as a promising structural-pharmacological building block for multifunctional hydrogel design and support SCG as an in situ-forming wound dressing for diabetic wound repair.