Hyperglycemia Targeting Nanomotors for Accelerated Healing of Diabetic Wounds by Efficient Microenvironment Remodeling

Abstract Multifunctional nanoagents are robust to remodel environments for managing chronic diabetic wounds. However, their delivery primarily relies on Brownian motion and randomly enhanced diffusion. Here, taking advantage of wound heterogeneity, such as the uneven distribution of glucose, hyperglycemia targeting nanomotors are proposed. They are capable of efficiently targeting hyperglycemic interfaces in diabetic wounds for significantly accelerating their healing by employing endogenous glucose‐activated cascade reactions and responding to local glucose gradients. Compared to previous counterparts, they show a four‐fold enhancement in effective coverage within 60 s and a multiplied accumulation at hyperglycemic interfaces, facilitating deep penetration. Correspondingly, the downregulation of glucose levels is apparently enhanced, while pH‐lowering and oxygen‐supplying are both improved. In comparison to the counterparts delivered by passive diffusion and randomly enhanced diffusion, the hyperglycemia targeting nanomotor‐based spray accelerates the wound healing upon diabetic mice by approximately 30% and 23%, resulting from the restricted inflammatory response, effective reactive oxygen species (ROS) scavenging and elevated vascular endothelial growth factor levels (VEGF). This study presents a generally efficient approach to facilitating the targeted delivery of nanoagents for the effective management of diabetic wounds by utilizing wound heterogeneity, which can be extended to other therapeutic systems.