Low-frequency ultrasound-driven piezoelectric films repair neuro-immune circuits in diabetic wound healing

• MXene/PVDF films act as acellular, cytokine-free dressings for diabetic wound healing. • Low-frequency ultrasound activates their piezoelectric properties, promoting neural repair. • Piezoelectric stimulation enhances axonal regeneration and CGRP neuropeptide secretion. • MXene/PVDF films induce CGRP secretion, driving macrophage M2 polarization for immune modulation. • MXene/PVDF films restore neuro-immune circuits, accelerating functional diabetic wound healing. Neuronal regeneration and immune modulation are critical for functional healing in diabetic wounds, yet existing wound treatments fail to address the complex interplay between these processes. This study introduces an effective cellular, cytokine-free therapeutic approach utilizing MXene/PVDF film for diabetic wound healing, driven by low-frequency ultrasound. These films provide localized electrical stimulation to enhance axonal regeneration and modulate immune responses within the wound microenvironment. Mechanistically, low-frequency ultrasound-activated MXene/PVDF films significantly promote axonal growth of dorsal root ganglion (DRG) explants, which, through the increased secretion of calcitonin gene-related peptide (CGRP) by peptidergic neurons, induce M2 macrophage polarization, thereby establishing neuro-immune circuits under hyperglycemic conditions. Macrophage depletion further confirms the crucial role of macrophages in facilitating neuronal regeneration. In vivo, the ultrasound-driven MXene/PVDF film accelerates wound healing, supports epidermal nerve regeneration and M2 macrophage polarization, and restores sensory function in diabetic wounds. These findings highlight the potential of MXene/PVDF films, coupled with ultrasound stimulation, as a promising therapeutic strategy for enhancing neuronal repair and immune modulation in diabetic wound healing.