Ultrasound-driven piezoelectric hydrogel enhances Schwann/neural stem cells Co-transplantation for spinal cord injury repair

• An innovative piezoelectric hydrogel-based platform is developed which integrates ultrasound-driven bioelectrical stimulation with co-delivery of NSCs/SCs. • Ultrasound-driven electrical stimulation can significantly promote the differentiation of NSCs into neurons, induce remyelination and enhanced neuronal synaptic remodeling. • This research establishes a paradigm-shifting approach that orchestrates biophysical (electrical) and biochemical (cellular) regulatory cues to reconstruct spinal cord circuitry. Spinal cord injury (SCI) remains a formidable clinical challenge due to the central nervous system’s limited regenerative capacity and the hostile microenvironment characterized by impaired axonal regeneration. Emerging therapeutic strategies employing co-transplantation of neural stem cells (NSCs) and Schwann cells (SCs) have shown promise through dual mechanisms of cellular replacement and neurotrophic factor delivery. However, suboptimal cell survival, incomplete neuronal differentiation, and the lack of endogenous electrophysiological cues persistently undermine therapeutic outcomes. To address these limitations, we developed an innovative piezoelectric hydrogel-based platform integrating ultrasound-driven bioelectrical stimulation with three-dimensional cellular co-delivery. This system leverages the unique properties of piezoelectric hydrogels to generate localized electrical fields under non-invasive ultrasound actuation, while simultaneously serving as a biomimetic scaffold for NSCs/SCs co-culture. In vitro analyses revealed that the piezoelectric stimulation significantly enhanced neuronal differentiation efficiency and promoted robust remyelination. In murine models of complete spinal cord transection, the synergistic system demonstrated multifaceted therapeutic effects: 1) enhanced NSCs-derived neuron survival, 2) increased synaptic density, and 3) accelerated motor function recovery. These findings establish a paradigm-shifting approach that orchestrates biophysical (electrical) and biochemical (cellular) regulatory cues to reconstruct spinal cord circuitry, offering new insights into developing multimodal neuroregenerative therapies for SCI.