Glucose oxidase-triggered cascade reaction in nanocomposite hydrogel for on-demand nitric oxide delivery and diabetic wound regeneration.

Diabetic wounds frequently exhibit prolonged healing and an increased risk of infection, which are largely attributed to hyperglycemia. Current biomaterials primarily focus on the inflammatory phase but fail to address the issue of persistent hyperglycemia at its root. Glucose-triggered cascade reactions are an emerging therapeutic strategy for wound healing. Herein, an injectable nanocomposite hydrogel (CTLG@HQ) based on cascade reactions has been developed to treat diabetic wounds via the consumption of local glucose and the sustained release of nitric oxide (NO). Glucose oxidase (GOx) and l-arginine (L-Arg) were loaded into the metal-polyphenol network (CT) formed by tannic acid (TA) and cerium (Ce) ions, thereby forming a cascade-responsive nanoplatform (CTLG). CTLG was incorporated into the aldehyde-modified hyaluronic acid (AHA) and quaternary chitosan (QCS) based hydrogel. CTLG first consumed glucose through the enzymatic action of GOx under high-glucose conditions, and the nonenzymatic pathway of L-Arg sequentially converted hydrogen peroxide into NO in situ, thereby producing antibacterial effects. Furthermore, CTLG@HQ could alleviate inflammation, regulate macrophage polarization and enhance angiogenesis, as well as promote collagen deposition and granulation tissue formation for treating diabetic wounds. Overall, CTLG@HQ offers a promising strategy to treat diabetic wounds through hyperglycemia-responsive cascade reaction.