Advancing Drug Delivery Through Complex Physiological Barriers in the Brain, Lymph Node, and Placenta.

More than 90% of central nervous system-directed drug candidates fail because they never reach the brain, and similarly formidable physiological tissue barriers protect the placenta and lymph node. These tissues are walled off by tight junctions, efflux pumps, and immune sentinels that thwart both endogenous and exogenous agents, complicating disease treatment. Here, we detail the microanatomy, transport mechanisms, and pathological shifts of the blood-brain, blood-lymph node, and maternal-fetal barriers. We then benchmark emerging solutions, from receptor-targeted nanoparticles and stimulus-responsive carriers to cell-mediated and bioderived vehicles, against the current landscape of US Food and Drug Administration-approved and experimental therapeutics. By comparing the relatively advanced blood-brain barrier delivery techniques to the immature landscape of lymph node and placental drug delivery, we can advance investigation of these tissues quicker. Leveraging tissue-specific physiology promises higher therapeutic indices, lower systemic toxicity, and faster clinical success and illuminates the priority questions that must be answered over the next decade.