Targeting m6A demethylase FTO to heal diabetic wounds with ROS-scavenging nanocolloidal hydrogels.

Chronic diabetic wounds are a prevalent and severe complication of diabetes, contributing to higher rates of limb amputations and mortality. N6-methyladenosine (m6A) is a common RNA modification that has been shown to regulate tissue repair and regeneration. However, whether targeting m6A could effectively improve chronic diabetic wound healing remains largely unknown. Here, we found a significant reduction in mRNA m6A methylation levels within human diabetic foot ulcers, and the expression level of fat mass and obesity-associated protein (FTO) was significantly increased. We identified that m6A modifies the RNA of matrix Metalloproteinase 9 (MMP9), a key factor in diabetic wound healing, to regulate its expression. Importantly, we developed a ROS-scavenging nanocolloidal hydrogel loaded with an FTO inhibitor to increase the m6A level of MMP9 RNA in wounds. The hydrogel can effectively accelerate wound healing and skin appendage regeneration in streptozotocin-induced type I diabetic rats at day 14 (approximately 98 % compared to 76.98 % in the control group) and type II diabetic db/db mice at day 20 (approximately 93 % compared to 60 % in the control group). Overall, our findings indicate that targeting m6A with ROS-scavenging hydrogel loaded with FTO inhibitor may be an effective therapeutic strategy for diabetic wound healing.