Crossing the Blood–Brain Barrier: Drug Development Strategies for Central Nervous System Disorders

The Blood-Brain Barrier (BBB) is a highly selective interface that protects the brain by regulating the entry of nutrients, signaling molecules, and potential toxins. The neurovascular unit (NVU), composed of endothelium, pericytes, and astrocytes, further modulates transport and barrier function. While essential for maintaining neural homeostasis, this physiology limits the brain penetration of many therapeutic molecules. Advances in receptor-mediated transcytosis, carrier-mediated transport, nanocarriers, and chemical modification strategies have begun to address these challenges. Additionally, innovations in in vitro and in vivo modeling, imaging, and biomarker development provide tools to assess and optimize CNS delivery. A comprehensive understanding of BBB/NVU biology, disease-state modulation, and transport mechanisms is critical for developing therapies capable of achieving therapeutic concentrations in the CNS. This Research Topic provides a forum for exploring such strategies across diverse drug modalities and CNS disorders.This Research Topic addresses the persistent challenge of CNS drug delivery by highlighting strategies to improve therapeutic exposure in the brain. Despite advances in drug discovery, many molecules fail not because of target biology but due to limited BBB penetration, resulting in late-stage attrition. This collection aims to showcase research that translates mechanistic understanding of the BBB/NVU into actionable development decisions, including transport hypothesis selection, molecular optimization, and formulation design. By emphasizing approaches that integrate discovery and delivery, such as BBB-aware medicinal chemistry, antibody and peptide vectors, or gene therapy strategies with clear biodistribution and functional validation, the topic seeks to advance CNS drug development. Contributions that employ quantitative and predictive methodologies linking CNS exposure to pharmacology are particularly encouraged, as they can inform design rules that generalize across multiple CNS indications and reduce late-stage failure.We invite Original Research, Reviews, Mini-Reviews, Methods, and Perspectives that focus on enhancing BBB/NVU penetration and CNS exposure. Submissions should clearly articulate how the proposed strategy advances CNS drug discovery and development. Topics of interest include, but are not limited to:• BBB and NVU mechanisms relevant to drug delivery (endo-/transcytosis, transporter biology, barrier regulation)• Antibodies and fragments engineered for CNS transport, including shuttle concepts• Peptides and proteins as therapeutics or targeting vectors, including intracellular trafficking considerations• Gene therapy and viral or non-viral delivery strategies• Drug delivery and formulation approaches: nanocarriers, prodrugs and controlled release• Medicinal chemistry and natural products enabling CNS exposure• Structure-based lead optimization• Bioinformatics or omics approaches to predict transport success and disease-state barrier effects.Emphasis is placed on translational relevance, mechanistic insight, and quantitative approaches that inform actionable design strategies. Topic editors: Rijwan U. Ahammad, Simona Rapposelli, Massimiliano Runfola Source: https://www.frontiersin.org/research-topics/78005/crossing-the-blood-brain-barrier-drug-development-strategies-for-central-nervous-system-disorders