Promoting Angiogenesis in Oxidative Diabetic Wound Microenvironment Using a Nanozyme-Reinforced Self-Protecting Hydrogel

Impaired diabetic wound healing represents a devastating and rapidly growing clinical problem associated with high morbidity, mortality, and recurrence rates. Engineering therapeutic angiogenesis in the wounded tissue is critical for successful wound healing. However, stimulating functional angiogenesis of the diabetic wound remains a great challenge, due to the oxidative damage and denaturation of bio-macromolecule-based angiogenic agents in the oxidative diabetic wound microenvironment. Here, we present a unique seed-and-soil strategy that circumvents the limitation by simultaneously reshaping the oxidative wound microenvironment into a proregenerative one (the soil) and providing proangiogenic miRNA cues (the seed) using an miRNA-impregnated, redox-modulatory ceria nanozyme-reinforced self-protecting hydrogel (PCN-miR/Col). The PCN-miR/Col not only reshapes the hostile oxidative wound microenvironment, but also ensures the structural integrity of the encapsulated proangiogenic miRNA in the oxidative microenvironment. Diabetic wounds treated with the PCN-miR/Col demonstrate a remarkably accelerated wound closure and enhanced quality of the healed wound as featured by highly ordered alignment of collagen fiber, skin appendage morphogenesis, functional new blood vessel growth, and oxygen saturation.