Enzyme-Flavonoid Synergistic Hydrogel: Enables Glucose-Activated Cascade Acidification and Programmed Drug Release for Diabetic Wound Therapy

Inflammation and oxidative stress induced by high glucose levels constitute essential factors impeding wound healing in diabetes, posing a significant threat to public health. Despite its notable anti-inflammatory and antioxidant potential, the clinical applicability of quercetin is hampered by its hydrophobicity and limited oral bioavailability. To address these issues, the thin-film hydration method was used to encapsulate quercetin into FQ micelles. Subsequently, 3-aminophenylboronic acid-modified oxidized alginate was crosslinked with polyvinyl alcohol, and simultaneously loaded with glucose oxidase (GOX) and FQ micelles, to construct a glucose-activated cascade acidification-triggered controlled-release hydrogel (OSSP@FQ&GOX). The phenylboronic ester bonds in the hydrogel are responsive to glucose and undergo cleavage. GOX-mediated oxidation of glucose produces gluconic acid, resulting in a lower local pH and subsequently triggering FQ micelle release. The released FQ micelles alleviate oxidative stress and exert immunomodulatory effects, while the hydrogel also provides self-healing, and biocompatible properties that facilitate cutaneous regeneration in diabetic mice. Thus, this study highlights the potential of combining GOX with natural products and multi-stimuli-responsive hydrogels for the treatment of chronic diabetic wounds, while also opening new avenues for the development of multifunctional wound dressings.