Cracking the Blood–Brain Barrier Code: Rational Nanomaterial Design for Next-Generation Neurological Therapies
Lucio Nájera-Maldonado, Mariana Parra-González, Esperanza Peralta-Cuevas, Ashley J. Gutierrez-Onofre, Igor Garcia-Atutxa, Francisca Villanueva‐Flores
Abstract
This review provides a mechanistic framework to strategically design nanoparticles capable of efficiently crossing the blood-brain barrier (BBB), a critical limitation in neurological treatments. We systematically analyze nanoparticle-BBB transport mechanisms, including receptor-mediated transcytosis, adsorptive-mediated transcytosis, and transient barrier modulation. Essential nanoparticle parameters (size, shape, stiffness, surface charge, and biofunctionalization) are evaluated for their role in enhancing brain targeting. For instance, receptor-targeted nanoparticles can significantly enhance brain uptake, achieving levels of up to 17.2% injected dose per gram (ID/g) in preclinical glioma models. Additionally, validated preclinical models (human-derived in vitro systems, rodents, and non-human primates) and advanced imaging techniques crucial for assessing nanoparticle performance are discussed. Distinct from prior BBB nanocarrier reviews that primarily catalogue mechanisms, this work (i) derives quantitative 'design windows' (size 10-100 nm, aspect ratio ~2-5, near-neutral ζ) linked to transcytosis efficiency, (ii) cross-walks human-relevant in vitro/in vivo models (including TEER thresholds and NHP evidence) into a translational decision guide, and (iii) integrates regulatory/toxicology readiness (ISO 10993-4, FDA/EMA, ICH) into practical checklists. We also curate recent (2020-2025) %ID/g brain-uptake data across lipidic, polymeric, protein, inorganic, and hybrid vectors to provide actionable, evidence-based rules for BBB design.