Dual-layer microneedles with NO/O2 releasing for diabetic wound healing via neurogenesis, angiogenesis, and immune modulation

Diabetic wounds present multiple functional impairments, including neurovascular dysregulation, oxidative imbalance, and immune dysfunction, making wound healing particularly challenging, while traditional therapeutical strategies fail to address these complex issues effectively. Herein, we propose a strategy utilizing dual-layer microneedles to deliver therapeutic gases by modulating neurovascular coupling and immune functions for diabetic wound treatment. The microneedle can respond to reactive oxygen species (ROS) in the diabetic microenvironment and subsequently generate oxygen (O 2 ) and nitric oxide (NO). These gases comprehensively promote neuro-vascular regeneration, reduce oxidative stress levels, and attenuate inflammation. In vivo studies demonstrate that the microneedle can accelerate diabetic wound healing by modulating neurovascular regeneration and inflammatory processes. Transcriptomic analyses further validate the involvement of related advantageous signaling pathways. The potential mechanism involves the activation of the PI3K-AKT-mTOR pathway to facilitate autophagy, ultimately accelerating the healing process. Thus, our multifunctional dual-layer microneedles provide an effective strategy for treating diabetic wounds. • Our study emphasized the critical role of nerve regeneration in diabetic wounds. • We developed a novel microneedle for multifacetedly promoting diabetic wound healing. • We demonstrated that delivering O₂ and NO gases can facilitate nerve regeneration. • The microneedle held strong potential for clinical application for diabetic wounds.