Trojan Horse Strategy for Wireless Electrical Stimulation-Induced Zn²⁺ Release to Regulate Neural Stem Cell Differentiation for Spinal Cord Injury Repair

Due to the uncertain differentiation of neural stem cells (NSCs), replenishing lost neurons by endogenous neural differentiation to repair spinal cord injury (SCI) remains challenging. The electrical stimulation-induced drug release is a promising approach for the localized and controlled release of drugs to regulate the differentiation of NSCs into neurons. Here, we developed Zn-PDA@BT nanoparticles acted as Trojan Horse to enter cells through endocytosis for Zn²⁺-controlled release therapy by the potentials generated by the piezoelectric effect. Due to the presence of polydopamine (PDA), under ultrasound stimulation, the electrical signal derived from the piezoelectric effect of barium titanate nanoparticles can be attracted to the surface of Trojan Horse nanoparticles to facilitate the controlled release of Zn²⁺. And Zn²⁺ bonded with PDA can increase the intracellular Zn²⁺ concentration within mouse-derived NSCs (mNSCs) to regulate the differentiation of mNSCs, which could enhance excitatory neuronal differentiation and inhibit astrocyte differentiation of mNSCs by activating the TGF-β and p53 pathways. More importantly, this Trojan Horse therapy allowed mNSCs to differentiate into mature neurons in 5 days, while the natural differentiation process took 10 days. Moreover, the transplantation of mNSC-ingested Zn-PDA@BT nanoparticles effectively replenished lost neurons at the damaged site and promoted function recovery after SCI in vivo, demonstrating the great potential of electrical stimulation-induced Zn²⁺ release for SCI repair.