Photodriven nanoreactor with a hydrogen-insulin double act repairs diabetic wounds through Nrf2 pathway activation

Abstract

Diabetic skin wounds remain the leading cause of lower limb amputation worldwide due to delay and difficulty in healing, and the etiology of these wounds often involves hyperglycemia-induced excessive reactive oxygen species production and sustained inflammation. Herein, a photodriven nanoreactor is constructed that incorporates both the in situ synthesis of therapeutic gaseous hydrogen and the release of bioactive insulin in the wound. The in situ release of hydrogen not only scavenges excessive reactive oxygen species but also relieves the inhibition of insulin signaling induced by hyperglycemia-driven overproduction of reactive oxygen species, thus reducing proinflammatory cytokine expression and wound tissue inflammation. Furthermore, topical administration of the nanoreactor to diabetic rat wounds significantly mitigates oxidative stress and inflammation, which is accompanied by increased collagen deposition, angiogenesis, and granulation tissue formation, resulting in the effective healing of diabetic wounds. In addition, the studies of the mechanism of action demonstrate that the nanoreactor activates the Nrf2 pathway, thereby exhibiting significant antioxidative stress and anti-inflammatory capabilities. Overall, this work opens up a new approach for efficiently supplying hydrogen and insulin to wound tissues in situ and provides a promising strategy for enhanced diabetic wound healing.