Enhancing angiogenesis is the prime target of current biomaterial-based wound healing strategies. However, these approaches largely overlook the angiogenic role of the cells of the nervous system. Therefore, we explored the role of a collagen-chondroitin sulfate scaffold functionalized with a proangiogenic gene stromal-derived factor-1 alpha (SDF-1 alpha)-an SDF-1 alpha gene-activated scaffold on the functional regulation of human Schwann cells (SCs). A preliminary 2D study was conducted by delivering plasmids encoding for the SDF-1 alpha gene into a monolayer of SCs using polyethyleneimine-based nanoparticles. The delivery of the SDF-1 alpha gene into the SCs enhanced the production of proangiogenic vascular endothelial growth factor (VEGF). Subsequently, we investigated the impact of SDF-1 alpha gene-activated scaffold (3D) on the SCs for 2 weeks, using a gene-free scaffold as control. The transfection of the SCs within the gene-activated scaffold resulted in transient overexpression of SDF-1 alpha transcripts and triggered the production of bioactive VEGF that enhanced endothelial angiogenesis. The overexpression of SDF-1 alpha also caused transient activation of the transcription factor c-Jun and supported the differentiation of SCs towards a repair phenotype. This was characterized by elevated expression of neurotrophin receptor p75NGFR. During this developmental stage, the SCs also performed an extensive remodelling of the basement matrix (fibronectin, collagen IV, and laminin) to enrich their environment with the pro-neurogenic matrix protein laminin, revealing an enhanced pro-neurogenic behavior. Together, this study shows that SDF-1 alpha gene-activated scaffold is a highly bioinstructive scaffold capable of enhancing proangiogenic regenerative response in human SCs for improved wound healing.