A 3D brain-mimicking hydrogel/graphene composite scaffold loaded with MSC-derived small extracellular vesicles promotes differentiation of neural stem cells

Central nervous system (CNS) diseases, characterized by irreversible neuronal damage, pose global health challenges with limited therapeutic options. Stem cell therapy, particularly using neural stem cells (NSCs), is promising with some constraints related to poor microenvironmental simulation. This study presents a composite scaffold integrating three-dimensional graphene foam (3D-GF), GelMA-PEG hydrogel, and mesenchymal stem cell derived small extracellular vesicles (sEVs) to mimic the brain's mechanical and electrical microenvironment while delivering bioactive factors. The hydrogel (<3 kPa) matches brain elasticity (0.5–5 kPa), 3D-GF provides a conductive neural network-like structure, and sEVs enhance neuronal differentiation. In vitro experimental results demonstrated that the NSCs in the composite scaffolds exhibited a proliferation efficiency approximately 7-fold (43.82 ± 2.34 %) higher than that of the control group while the differentiation efficiency was enhanced by 3-fold (49.56 ± 7.80 %). The scaffold's design facilitates mechanical support, electrical signal transduction, and molecular regulation, effectively offering a biomimetic microenvironment. This multi-modal scaffold overcomes traditional limitations, presenting a biomimetic strategy for CNS repair in degenerative diseases.