A multimodal perspective to overcome translational barriers in cerebrospinal drug delivery

Translating preclinical findings in human neurological drug delivery remains a challenge, particularly for molecules administered directly into cerebrospinal fluid (CSF) via intrathecal, intracisternal, or intracerebroventricular routes. Anatomical and physiological disparities between animal models and the human neuroaxis complicate extrapolation of pharmacokinetic and pharmacodynamic data.

This review synthesizes expert perspectives on translational barriers of CSF-mediated delivery. The review focuses on macroscopic aspects such as delivery methods, CSF flow, and neuroanatomical features, while remaining agnostic of specific drugs or injectates. While physiological processes such as neuronal uptake inform CNS biodistribution, they are drug-specific and beyond this review's scope.Using a hypothesis-driven framework, literature was analyzed and categorized into themes: Preclinical-to-Human Translation, Neuroimaging, and CSF Flow Characterization (Theoretical, Experimental, Clinical). Strategic approaches identified include leveraging neuroimaging technologies and adopting tiered, multi-species modeling to better approximate human CNS dynamics. The glymphatic system and parameters for enhancing parenchymal distribution are highlighted as promising pathways. We recommend integrative frameworks that combine imaging, modeling, and biological validation.

We propose a roadmap emphasizing harmonized imaging and multimodal modeling to investigate CNS delivery modalities. These foundational steps are essential for bridging preclinical and clinical gaps and accelerating the development of next-generation CNS delivery platforms.