Regeneration of injured nerve tissues requires intricate interplay of complex processes like axon elongation, remyelination, and synaptic formation in a tissue‐specific manner. A decellularized nerve matrix‐gel (DNM‐G) and a decellularized spinal cord matrix‐gel (DSCM‐G) are prepared from porcine sciatic nerves and spinal cord tissue, respectively, to recapitulate the microenvironment cues unique to the native tissue functions. Using an in vitro dorsal root ganglion–Schwann cells coculture model and proteomics analysis, it is confirmed that DNM‐G promotes far stronger remyelination activity and reduces synapse formation of the regenerating axons in contrast to DSCM‐G, Matrigel, and collagen I, consistent with its tissue‐specific function. Bioinformatics analysis indicates that the lack of neurotrophic factors and presence of some axon inhibitory molecules may contribute to moderate axonal elongation activity, while laminin β2, Laminin γ1, collagens, and fibronectin in DNM‐G promote remyelination. These results confirm that DNM‐G is a promising matrix material for peripheral nerve repair. This study provides more insights into tissue‐specific extracellular matrix components correlating to biological functions supporting functional regeneration.

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The mechanism underlying neurogenesis during embryonic spinal cord development involves a specific ligand/receptor interaction, which may be help guide neuroengineering to boost stem cell-based neural regeneration for the structural and functional repair of spinal cord injury. Herein, we hypothesized that supplying spinal cord defects with an exogenous neural network in the NT-3/fibroin-coated gelatin sponge (NF-GS) scaffold might improve tissue repair efficacy. To test this, we engineered tropomyosin receptor kinase C (TrkC) -modified neural stem cell (NSC)-derived neural network tissue with robust viability within an NF-GS scaffold. When NSCs were genetically modified to overexpress TrkC, the NT-3 receptor, a functional neuronal population dominated the neural network tissue. The pro-regenerative niche allowed the long-term survival and phenotypic maintenance of the donor neural network tissue for up to 8 weeks in the injured spinal cord. Additionally, host nerve fibers regenerated into the graft, making synaptic connections with the donor neurons. Accordingly, motor function recovery was significantly improved in rats with spinal cord injury (SCI) that received TrkC -modified NSC-derived neural network tissue transplantation. Together, the results suggested that transplantation of the neural network tissue formed in the 3D bioactive scaffold may represent a valuable approach to study and develop therapies for SCI.