Shape as an Independent Design Parameter for Blood–Brain Barrier Crossing: Anisotropic Nanoparticles in Neurodegenerative Diseases

Background: Neurodegenerative diseases (NDDs) impose a growing burden, yet effective therapy remains limited because the blood–brain barrier (BBB) restricts CNS drug delivery. Existing reviews treat particle geometry as secondary to composition, size, and surface functionalization. Objectives: This review examines shape anisotropy as an independent design parameter for BBB crossing, arguing that non-spherical geometry qualitatively changes the logic of particle–barrier interaction. Methods: As a narrative review, it synthesizes studies comparing anisotropic and spherical particles of comparable size and surface chemistry, with emphasis on mechanistic evidence linking geometry to transport. Findings: Geometry governs adhesion under flow, membrane wrapping, endocytic route multiplicity, and intracellular trafficking. A barrier-crossing versus penetration-depth trade-off is identified: efficient transcytosis and deep parenchymal distribution are mutually exclusive. The same anisotropy that enhances BBB interaction also reduces its predictability—the “paradox of shape”—owing to the protein corona, endothelial heterogeneity, and disease-altered barrier status. Conclusions: Shape is not a universal “key to the BBB” but a controllable, context-dependent parameter, shifting the field from an optimal geometry toward disease-oriented, robustness-based design.