Cascade-Therapeutic Nanozyme Hydrogel Mediates Hypoxia Alleviation and Angiogenesis Promotion To Accelerate Diabetic Wound Healing

Abstract

Diabetic wounds exhibit prolonged inflammation and excessive oxidative stress, impairing tissue repair. Chronic hypoxia arises from vascular dysfunction and metabolic dysregulation, creating a pathological cycle of oxidative damage, defective angiogenesis, and persistent inflammation. To address these challenges, we develop the multifunctional rosmarinic acid-cerium nanozyme (RA-Ce NP) hydrogel composites designed for diabetic wound therapy. The system integrates RA-Ce NPs, phenylboronic acid-grafted poly-l-lysine, and oxidized hyaluronic acid into a dynamically crosslinked hydrogel network through Schiff base and boronate ester linkages. Both in vitro and in vivo studies demonstrate that the hydrogel enables multienzyme mimicry for synergistic reactive oxygen species scavenging, controlled oxygen generation to relieve tissue hypoxia, and promotion of neovascularization. Our work provides a clinically translatable platform for diabetic wound therapy, offering antibacterial, anti-inflammatory, and angiogenesis-promoting functions.