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Local delivery of neurotrophic factors is a pillar of neural repair strategies in the peripheral nervous system. The main disadvantage of the free growth factors is their short half‐life of few minutes. In previous studies, it was demonstrated that conjugation of various neurotrophic factors to iron oxide nanoparticles (IONP) led to stabilization of the growth factors and to the extension of their biological activity compared to the free factors. In vitro studies performed on organotypic dorsal root ganglion (DRG) cultures seeded in NVR gel (composed mainly of hyaluronic acid and laminin) revealed that the glial cell–derived neurotrophic factor (GDNF) conjugated to IONP‐enhanced early nerve fiber sprouting and accelerated the onset and progression of myelin significantly earlier than the free GDNF and other free and conjugated factors. The present article summarizes results of in vivo study, aimed to test the effect of free versus conjugated GDNF on regeneration of the rat sciatic nerve after a severe segment loss. We confirmed that nerve device enriched with a matrix with GDNF gives more successful results in term of regeneration and functional recovery in respect to the hollow tube; moreover, there are no detectable differences between free versus conjugated GDNF.