Skin-mimetic bilayer hydrogel enhances spatiotemporal coordination of neuro-immune-vascular interactions to accelerate diabetic wound healing

Diabetic wound healing is a complex spatiotemporal process that requires stage-specific interventions to address disrupted neuro-immune interactions and impaired angiogenesis. However, achieving such precise coordination with a single regenerative dressing remains a considerable challenge. Drawing inspiration from native skin physiology, we have developed an intelligent, conductive, skin-mimetic bilayer hydrogel that spatially segregates functions and temporally orchestrates the repair process. This design features a robust, anisotropic upper layer that provides protection and serves as an efficient conduit for electrical stimulation, combined with a responsive lower layer that adheres to the wound and enables on-demand drug delivery. Specifically, the lower hydrogel releases calcitonin gene-related peptide in response to the early inflammatory microenvironment, effectively suppressing the pro-inflammatory M1 macrophage phenotype and promoting its transition to the pro-repair M2 phenotype. Subsequently, the conductive upper layer sustains the release of magnesium ions and synergizes with electrical stimulation to significantly enhance endothelial cell migration and tube formation via activation of the VEGF signaling pathway. Transcriptomic analysis reveals that this combination fosters a pro-regenerative microenvironment by enriching pathways related to extracellular matrix organization and angiogenesis. This skin-mimetic structure-to-function design offers a practical strategy for staged, precise wound repair in diabetes and provides a generalizable framework for chronic tissue regeneration. This study presents a skin-mimetic bilayer hydrogel inspired by natural skin, comprising an anisotropic tough conductive upper layer and a responsive adhesive lower layer. It sequentially releases CGRP and Mg 2+ upon electrical stimulation to coordinate neuro-immune interactions and neurovascularization spatially and temporally. This neuro-immune-vascularization approach closely replicates the biological cascade of diabetic wound healing. • A skin-mimetic bilayer hydrogel enables spatially segregated, time-sequenced therapy for diabetic wound healing. • Combined adhesive and conductive layers modulate inflammation and regeneration without functional interference. • A CGRP-mediated neuro-immune-vascular cascade coordinates healing and angiogenesis in diabetic wounds.