Clinically, the therapeutic outcomes in neurodegenerative disorders (NDs) by drug treatment are very limited, and the most insurmountable obstacle in the treatment of NDs is the blood-brain barrier (BBB), which provides the highest level of protection from xenobiotics. A great deal of attention still needs to be paid to overcome these barriers, and surface-engineered polymeric nanoparticles are emerging as innovative tools that are able to interact with the biological system at a molecular level for the desired response. The present review covers the potential importance of surface-structure-engineered nanoparticles to overcome the BBB for good bioavailability, and the evaluation of drug therapy in NDs.