Recent evidences suggest that insulin delivery to the brain can be an important pharmacological therapy for some neurodegenerative pathologies, including Alzheimer disease (AD). Due to the presence of the Blood Brain Barrier, a suitable carrier and an appropriate route of administration are required to increase the efficacy and safety of the treatment. Here, poly(N-vinyl pyrrolidone)-based nanogels (NG), synthetized by e-beam irradiation, alone and with covalently attached insulin (NG-In) were characterized for biocompatibility and brain delivery features in a mouse model. Preliminarily, the biodistribution of the “empty” nanocarrier after intraperitoneal (i.p.) injection was investigated by using a fluorescent-labeled NG. By fluorescence spectroscopy, SEM and dynamic light scattering analyses we established that urine clearance occurs in 24 h. Histological liver and kidneys inspections indicated that no morphological alterations of tissues occurred and no immunological response was activated after NG injection. Furthermore, after administration of the insulin-conjugated nanogels (NG-In) through the intranasal route (i.n.) no alteration or immunogenic response of the nasal mucosa was observed, suggesting that the formulation is well tolerated in mouse. Moreover, an enhancement of NG-In delivery to the different brain areas and of its biological activity, measured as Akt activation levels, with reference to free insulin administration was demonstrated. Taken together, these results indicate that the synthesized NG-In enhances brain insulin delivery upon i.n. administration and strongly encourage its further evaluation as therapeutic agent against some neurodegenerative diseases.