Electroconductive and mechano-competent PUCL@CNT nanohybrid scaffolds guiding neuronal specification of neural stem/progenitor cells

Diseased or injured nervous systems lead to lifelong disability and even death due to their limited self-repair and regenerative capability. For successful neuronal regeneration and functional recovery, it is critical to selectively guide neural stem/progenitor cells (NSPCs) to differentiate into neurons and oligodendrocytes rather than astrocytes. Biomaterial scaffolds with specific properties such as electroconductivity can boost this event and guide the specific differentiation of NSPCs. Here, we prepared electroconductive and mechano-competent scaffolds made of shape-memory polyurethane‐polycaprolactone (PUCL) nanofibers and carbon nanotubes (CNTs) (namely, PUCL@CNT). The CNT-decorated PUCL platforms provided excellent shape-formable and shape-memorable properties for surgical compatibility as well as electroconductivity (∼ 8 S/m) and nanoscale-topography (tens-of-nm), which could promote the initial cell adhesion via the integrin-mediated focal adhesion signaling pathway, and promote neuron and oligodendrocyte differentiation. The potential mechanism of this lineage-specific differentiation of NSPCs upon the PUCL@CNT was evaluated by transcriptome sequencing analysis and pharmacological intervention tests, revealing the involvement of the intracellular calcium levels and the FAK-AKT-β-catenin pathway. When implanted in a rat corticectomy model, PUCL@CNT could induce a larger number of endogenous neural stem cells (both Nestin⁺ and β-catenin⁺) and neurons (Tuj1⁺) near the injured region (vs. PUCL and PBS), demonstrating the in vivo therapeutic role of PUCL@CNT. Taken together, the CNT surface-decoration was effective in driving NSPCs toward neuronal specification and their maturation, and the PUCL@CNT scaffold is potentially useful for neural tissue regeneration that can benefit via the neuronal activation of endogenous NSPCs.