David S. Hersh 1 , 2 , Aniket S. Wadajkar 1 , 2 , Nathan B. Roberts 1 , 2 , Jimena G. Perez 1 , 2 , Nina P. Connolly 1 , 2 , Victor Frenkel 2 , 3 , Jeffrey A. Winkles 2 , 4 , 5 , Graeme F. Woodworth 1 , 2 , * , Anthony J. Kim 1 , 2 , 6 , 7 , *
The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.