Recent advances in polymer science and nanotechnologies showed an increased interest for the nanogels (NGs), a new class of colloidal systems that, if properly functionalized, can be used as carriers of drugs to treat central nervous system diseases. Nanogels were synthesized using polyethylene glycol (PEG) and polyethylenimine linear (PEI), after having functionalized PEI with a chromophore using a “click” reaction. This PEI functionalization is essential for being able to constantly trace the nanogels during the biological assays. Many different coating strategies of the nanogels were analyzed: in fact, the surface functionalization is essential to tune the characteristics, and the biological behavior, of the final system. The NGs underwent characterization through dynamic light scattering analyses and drug release tests together with in vitro and in vivo biological assays. Biological tests proved that functionalized nanogels were able to be selectively internalized in mouse microglia or astrocytes depending on their surface decoration, that their degradation promoted drug release and the use of anti-inflammatory molecules as delivered drug were able to mitigate the pain state. In vivo subsequent assays on diseased mouse confirmed the result obtained in vitro and the potentiality of this kind of surface functionalization. Nanogels are for sure effective devices in controlled drug delivery and here we showed their potentialities as targeted drug delivery systems in central nervous system diseases.