Ultrasound-Activated Piezoelectric Neuroimmune Hydrogel Orchestrates Neurogenesis-Macrophage Crosstalk in Diabetic...

Chronic diabetic wounds remain a major clinical challenge due to persistent inflammation, impaired neuro-immune crosstalk, and dysregulated macrophage polarization. Here, we report an injectable, ultrasound (US)-activated piezoelectric hydrogel that programmably couples neurogenesis and macrophage reprogramming to accelerate diabetic wound repair. The hydrogel is constructed from dynamic covalent networks among acyl hydrazide hyaluronic acid, benzene boronic acid modified oxidized sodium alginate, and epigallocatechin 3-gallate, and integrates a neuroactive self-assembling peptide and piezoelectric PLLA nanofibers. This design confers the hydrogel with injectability, self-healing, tissue adhesion, and US-triggered electrical signaling. In vitro, the hydrogel under US promotes M2 macrophage polarization and enhances axonal outgrowth of dorsal root ganglion neurons, establishing bidirectional neurogenesis-macrophage crosstalk. In a type II diabetic mouse model, the hydrogel markedly accelerates wound closure, elevates the M2/M1 ratio, enhances reinnervation and angiogenesis, and improves collagen remodeling. Transcriptomic analysis of cells and wound tissues identifies coordinated regulation of mitochondrial function and oxidative phosphorylation as a central mechanism. In a diabetic rabbit ear model, the hydrogel with US further attenuates hypertrophic scar formation. This programmable piezoelectric hydrogel converts noninvasive US into spatially confined bioelectrical and biochemical cues, offering a promising strategy to overcome multifactorial barriers in diabetic wound healing.