Engineering smart ZnO-lignin-chitosan/cyanidin nanofibers for diabetic wound repair

Diabetic cutaneous wounds represent a major clinical challenge due to persistent inflammation, oxidative stress, infection, and impaired angiogenesis. Here, we developed a cyanidin-3-O-glycoside (Cy)-reinforced smart nanofiber (S-NFs) composed of zinc oxide (ZnO) nanoparticles, lignin, chitosan, and conductive polypyrrole (PPy) for advanced diabetic wound repair, validated in a diabetic cutaneous wounds model. The S-NFs exhibited uniform morphology, favorable mechanical properties, lysozyme-responsive degradation, and pH-dependent release kinetics governed by charge-based interactions, with zero-order release profiles at each fixed pH for both ZnO and Cy. In vitro, studies demonstrated excellent cytocompatibility, broad-spectrum antibacterial activity against S aureus and E coli , and significant reactive oxygen species (ROS) scavenging capacity. Mechanistically, S-NF promoted ROS scavenging and suppressed pro-inflammatory M1 markers (iNOS, TNF-α, CD86, NLRP3) in LPS/IFN-γ-stimulated RAW 264.7 macrophages, indicating a shift away from the inflammatory state. In a streptozotocin-induced diabetic mouse wound model, S-NFs treatment accelerated wound closure (> 90%), enhanced re-epithelialization, increased mature collagen deposition, and promoted angiogenesis, as evidenced by elevated VEGF and CD31 expression. Histological and immunohistochemical analyses confirmed reduced IL-6, α-SMA, and TGF-β levels, indicating successful transition from inflammation to proliferation. Importantly, S-NFs displayed no systemic toxicity in major organs or serum biochemistry. Collectively, this multifunctional S-NF platform offers a promising preclinical strategy for diabetic wound management by integrating antioxidant, antimicrobial, anti-inflammatory, and pro-angiogenic properties within a single biodegradable dressing.