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.