Neuroimmune Microenvironment Reprogramming via Immuno-piezoelectric Transducers for Synergistic Stem Cell Therapy in Traumatic Brain Injury.

Secondary traumatic brain injury (TBI) induces a pro-inflammatory microenvironment that hampers neural stem cells (NSCs) therapy and tissue regeneration. To address this challenge, an immuno-piezoelectric transducer have been developed to create an anti-inflammatory immune microenvironment, deliver wireless electrical stimulation, and facilitate multimodal NSCs therapy. The immuno-piezoelectric transducer drives the polarization of microglia towards the anti-inflammatory M2 phenotype and secretion of anti-inflammatory cytokines. This modulation significantly reduces the inflammatory response, creating an optimal microenvironment for NSCs survival. Furthermore, the wireless electrical stimulation generated by ultrasound facilitates NSCs differentiation into glutamatergic and GABAergic neurons, enhances neurite complexity, upregulates synaptic proteins expression and neural integration in injured regions. The multimodal therapy demonstrates superior outcomes in restoring structural integrity, improving functional, and enhancing behavioral action in TBI rat models. This study integrates piezoelectric with immunomodulation to reprogram the neuroimmune microenvironment, providing novel therapeutic paradigm for brain injury repair.