Providing topographical cues along with chemical and biological factors is essential for biomimetic scaffolds applied in nerve tissue engineering. The aim of the presented work was to study the synergistic effect of the surface's topography and biological stimulation using nerve growth factor (NGF) on the behavior of PC12 cells. Three types of scaffolds based on poly(L-lactide-co-caprolactone), collagen type I and collagen type III with aligned orientation of the fibers were fabricated by either blend or coaxial electrospinning. The chemical, physical and mechanical properties of the scaffolds were further evaluated and, at the same time, the influence of the NGF and BSA incorporation method on the release profile was investigated. Moreover, the NGF dependent PC12 cell response was analyzed. It was found that encapsulation of the growth factor within the core of core–shell nanofibers enables preservation of the growth factor bio-activity. On the other hand, nanofibers produced by co-axial electrospinning allowed for control and stable release, which can be described by the Higuchi and Korsmeyer–Peppas models. This results in PC12 interaction with the material, and it was observed that the cells differentiated more efficiently, expressing bi- and tri-polar elongations, retaining their typical phenotype, on core–shell scaffolds compared to the other ones utilized within this work. The presented studies indicate that poly(L-lactide-co-caprolactone), collagen type I and collagen type III scaffolds with aligned core–shell fibers are promising materials and can be applied as substrates for peripheral nerve regeneration.