Cracking the Blood–Brain Barrier Code: Rational Nanomaterial Design for Next-Generation Neurological Therapies

This review establishes a robust conceptual and mechanistic framework for rationally designing advanced nanobiotechnological systems explicitly tailored for efficient blood–brain barrier (BBB) translocation, addressing one of the most critical challenges in neurological drug delivery. We systematically dissect the mechanisms governing nanoparticle (NP)-BBB interactions, focusing on receptor-mediated transcytosis, adsorptive-mediated transcytosis, cell-mediated transport, and transient barrier modulation, based on recent cellular and preclinical pharmacokinetic studies. Key NP physicochemical parameters, including particle size, surface chemistry, shape, mechanical stiffness, and biofunctionalization strategies, are critically evaluated for their roles in pharmacological efficacy and precision targeting of neurological disorders. Moreover, validated preclinical models and cutting-edge imaging techniques, essential for assessing nanocarrier delivery efficiency and therapeutic performance, are comprehensively discussed. Ultimately, this review provides pharmaceutical researchers and formulation scientists with actionable insights and evidence-based guidelines for designing next-generation nanoformulations that can effectively deliver therapeutics to the brain, thereby significantly enhancing treatment outcomes for neurological diseases.