3D-Printed ROS-Scavenging and Immunomodulatory Hydrogel Accelerates Diabetic Wound Healing through Synergistic Microenvironment Regulation

Abstract The management of diabetic wounds remains clinically challenging, primarily owing to three interrelated pathological mechanisms: excessive accumulation of reactive oxygen species (ROS), dysregulated angiogenesis, and sustained, non-resolving inflammation. To address these issues, we developed a multifunctional 3D-printed nanoparticle enhanced bionic skin (3D-NEBS) by integrating polydopamine-gallium-arginine nanoparticles (PDA-Ga-LArg) into a self-healing hydrogel matrix composed of oxidized Tremella fuciformis polysaccharide, carboxymethyl chitosan, and fish gelatin. The resulting dressing exhibited mechanical adaptability, pH-responsive release, robust ROS-scavenging capacity and targeted immunomodulatory activity. In vitro, 3D-NEBS promoted M2 macrophage polarization, reduced inflammation, enhanced nitric oxide (NO) production, and improved endothelial cell migration and tube formation. Broad-spectrum efficacy was confirmed, with significant growth inhibition observed against S. aureus and E. coli. In a diabetic rat model, 3D-NEBS achieved 92.79% ± 0.39% wound closure within 14 days, with enhanced collagen deposition and neovascularization. Transcriptomic analysis revealed upregulation of pathways related to collagen synthesis, antioxidant response, and immune regulation. This study presents a synergistic hydrogel-nanoparticle platform with strong potential for diabetic wound repair.