Nanoparticles Navigating the Blood-Brain Barrier for Neurodegenerative Therapy.

The blood-brain barrier (BBB) blocks most drugs from entering the brain. Over 98% of small-molecule drugs and nearly all biologics fail to cross this barrier. Nanoparticles (NPs) provide multiple ways to bypass the BBB. These include receptor-mediated transcytosis, adsorptive-mediated transport, and intranasal delivery. NPs can also modify disease-related pathways. For example, they promote amyloid-β clearance, reduce tau phosphorylation, and reprogram neuroimmune responses. Many preclinical studies have shown promising results in Alzheimer's, Parkinson's, and Huntington's diseases. However, no NP-based therapy has moved beyond early-stage clinical trials. Several issues remain unresolved. Direct comparisons between different NP platforms are lacking. The long-term toxicity of NPs in the brain is not well understood. Animal models also do not accurately reflect human disease. We suggest that future work should focus on standardized characterization, better predictive models, and clinical trial designs that address NP diversity. Researchers should also compare NP therapies with existing treatments in a rigorous manner.