Highways to the Brain: Nanoformulations for the Treatment of Central Nervous System Pathologies

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Abstract
Central nervous system (CNS) disorders remain difficult to treat because many pharmacologically active molecules do not achieve adequate exposure in the brain. The blood–brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier, efflux transporters, extracellular matrix, and local clearance mechanisms impose different constraints according to the target compartment and administration route. Nanocarriers can protect unstable payloads, alter pharmacokinetics, and support receptor-mediated or local delivery, but the same properties that promote transport can also increase immune recognition, tissue retention, and neurotoxicity. This review critically examines how nanoparticles (NPs) size, surface charge, composition, degradability, ligand density, and release kinetics should be matched to intravenous, intranasal, intrathecal, intracranial, and oral administration. Rather than treating these routes as interchangeable, we compare the barriers encountered by each route, the payloads for which it is best suited, and the experimental conditions that limit interpretation of reported brain uptake. Particular attention is given to the weak correspondence between many rodent efficacy studies and human delivery constraints, including protein-corona formation after systemic dosing, species differences in BBB and nasal anatomy, limited parenchymal penetration from cerebrospinal fluid, and the procedural risks of direct administration. The resulting route-specific framework is intended to support application-driven formulation design and more informative preclinical evaluation of CNS nanomedicines.
Funding Information
  • #NEXTGENERATIONEU
  • Ministry of University and Research (project MNESYS (PE0000006)—A multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).)
  • Italian Ministry of Health

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