Delivery of nanoparticles and macromolecules across the blood–brain barrier

Treatment of brain-related diseases is challenging due to the presence of the blood-brain barrier (BBB), a hurdle that prevents most foreign matter from entering the brain. While macromolecules and nanoparticles represent an increasing fraction of the therapeutic landscape in general, their limited ability to cross the BBB has hindered their clinical impact in treating diseases of the central nervous system. Here, the various routes for entry of macromolecular therapeutics into the brain are discussed, as well as the methods used to enhance their transport. Particular emphasis is placed on highlighting quantitative trends and mechanistic insights into how the macromolecular transport can be improved, discussing novel enhancement strategies, and identifying areas in need of more detailed investigations. Overall, this review shows several promising advances and continued progress toward a more complete understanding of how macromolecule and nanoparticle design and delivery strategy characteristics can be leveraged to improve the treatment of brain diseases.