Nanoparticle-Mediated Regulation of Intracellular Ferric Ions to Induce Motor Neuron Differentiation for Spinal Cord Injury Repair

Stem cell therapy is a prospective approach to the treatment of spinal cord injury (SCI), which features grievous harm of motor and sensory functions. However, the proportion of motor neurons spontaneously differentiated from neural stem cells (NSCs) is insufficient to form functional neural networks, resulting in a poor therapeutic effect of NSCs for SCI repair. Herein, we report that regulating the intracellular concentration of ferric ions (Fe³⁺) enables directed differentiation of NSCs into motor neurons. This process relies on the endocytosis of ferric oxide (Fe₂O₃) nanoparticles by NSCs and their lysosomal decomposition under acidic conditions. The endocytosis of Fe₂O₃ nanoparticles increases the intracellular concentration of Fe³⁺, promoting the differentiation of NSCs into mature neurons 5 days earlier compared to the spontaneous differentiation of NSCs. Moreover, the increased intracellular Fe³⁺ induces the specific differentiation of 29.38% of NSCs into motor neurons. In vivo experiments reveal that the NSCs preuptake with Fe₂O₃ nanoparticles improve the motor and sensory function recovery of SCI mice. This work overcomes a major challenge in directing the differentiation of NSCs into motor neurons and offers significant promise for enhancing NSC therapy for SCI.