Ultrasound-activated piezoelectric nanostickers for neural stem cell therapy of traumatic brain injury

Traumatic brain injury (TBI) is associated with life-threatening and permanent disabilities. Given the limited capacity of neurons to regenerate, effective treatments for TBI are lacking. Neural stem cells (NSCs) can differentiate into fully functioning neurons and thus hold promise for TBI treatment. Nonetheless, NSC differentiation and proliferation are slow and inefficient. Studies have shown that piezoelectric stimulation is capable of promoting the differentiation and proliferation of NSCs. Here, we describe barium titanate-reduced graphene oxide (BTO/rGO) hybrid piezoelectric nanostickers that promote NSC proliferation and differentiation. These hybrid nanostickers attach to NSC membranes, serving as long-term generators of piezoelectric potentials upon ultrasound stimulation. BTO/rGO nanostickers promote rapid neuronal differentiation and maturation by activating the voltage-gated calcium channel/Ca²⁺/calmodulin-dependent protein kinase II/cAMP response element-binding protein pathways. Transplantation of NSCs with BTO/rGO nanostickers into the injured brain region of rats with TBI substantially repairs brain tissue and effectively restores physiological functions after 28 d following 5-min ultrasound irradiation every 2 d. These results demonstrate the potential of the combination of NSCs and BTO/rGO nanostickers for TBI treatment.