A variety of therapeutic
proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these
protein molecules to the brain is well known.
Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to
proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering
proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of
protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of
protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of
proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased
protein delivery to the brain in relevant models of
CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of
protein delivery to the brain and aim developing and studying effective brain delivery systems for
protein therapeutics.