Effective intervention is essential to combat the coming epidemic of neurodegenerative (ND) diseases. Nanomedicine can overcome restrictions of CNS delivery imposed by the blood–brain barrier, and thus be instrumental in preclinical discovery and therapeutic intervention of ND diseases. Polymeric nanoparticles (PNPs) have shown great potential and versatility to encapsulate several compounds simultaneously in controlled drug-delivery systems and target them to the deepest brain regions. Here, we critically review recent advances in the development of drugs incorporated into PNPs and summarize the molecular changes and functional effects achieved in preclinical models of the most common ND disorders. We also briefly discuss the many challenges remaining to translate these findings and technological advances successfully to current clinical settings.