Effective diabetic wound prohealing by supramolecular ROS-responsive hyaluronic acid hydrogels <i>via in situ</i> production of nitric oxide and oxygen

The wound dressings currently in use have difficulties in addressing chronic inflammation and hypoxia for refractory diabetic wound prohealing. Aiming to regulate the inflammatory and hypoxic microenvironment in diabetic wounds, supramolecular reactive oxygen species (ROS)-responsive hyaluronic acid (HA) hydrogels were constructed by using salt bridge H-bonding and metal-ion coordination interactions among HA, L-arginine (Arg) and trivalent metal ions, where HA/Arg/Ce presented ROS-responsive nitric oxide (NO) and O₂ co-release behavior. <i>In vitro</i> and <i>in vivo</i> biological assays demonstrated that the lead hydrogel of HA/Arg/Ce effectively eliminated excessive ROS, polarized inflammatory M1 macrophage transition to prohealing M2 phenotype, and accelerated full-thickness skin wound healing in diabetic rats. Excitingly, single-dose treatment of HA/Arg/Ce achieved high-performance diabetic wound healing, including optimal re-epithelialization and dermis regeneration, 82.3% collagen deposition, ∼2.5-fold hair follicles and ∼3.0-fold skin tensile strength compared to Tegaderm. Significantly, this work provides a versatile strategy for the preparation of supramolecular HA hydrogels with long-acting NO/O₂ co-release properties for potential translation in chronic diabetic wound dressings.