Mitochondrion‐Targeting Piezoelectric Nanocomposite Hydrogels for Spinal Cord Injury Repair via Directing Neuronal Differentiation of Neural Stem Cells

Abstract Neural stem cells (NSCs) transplantation represents a promising therapeutic strategy for spinal cord injury (SCI). However, the acquisition of functional neurons through their natural differentiation is limited and maintaining the viability of implanted NSCs poses significant challenges. In this study, based on barium titanate (BTO), polydopamine (PDA), and triphenylphosphine (TPP), mitochondria‐targeted piezoelectric nanoparticles (TPP‐PDA@BTO) are synthesized and an injectable piezoelectric nanocomposite hydrogel (BT‐Gel) is developed responsive to reactive oxygen species (ROS). The TPP‐PDA@BTO loaded within BT‐Gel effectively promotes NSCs neural differentiation under ultrasound (US) irradiation, a process confirmed by transcriptomic sequencing to be closely associated with the enhanced mitochondrial function in NSCs due to piezoelectric stimulation targeting mitochondria. Additionally, BT‐Gel under US significantly facilitates the M2 polarization of microglia and enhances myelinated axons regeneration. The bioactive hydrogel also effectively promotes the integration of transplanted NSCs with host neural circuits, supplemented damaged neurons, alleviated neuroinflammation, and inhibited glial scar formation, thereby significantly accelerating the recovery of motor function of SCI rats. Therefore, mitochondrion‐targeting piezoelectric nanocomposite hydrogel capable of delivering NSCs, based on the therapeutic concept of promoting neural differentiation of exogenous NSCs and comprehensively regulating the pathological microenvironment post‐SCI, offers a novel perspective for stem cell therapy in central nervous system injuries.