Nanotechnology-Based Drug Delivery Across the Blood-Brain Barrier in Neurodegenerative Diseases

Abstract

Background: Neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, and related dementias are major causes of progressive disability, dependency, caregiver burden, and long-term health-system pressure. Therapeutic development is limited not only by disease complexity but also by poor central nervous system delivery, as the blood-brain barrier restricts the entry of many hydrophilic drugs, peptides, proteins, antibodies, enzymes, and nucleic-acid-based therapies. Objective: This structured narrative review synthesized current evidence on nanotechnology-based drug delivery across, around, or through transient modulation of the blood-brain barrier in neurodegenerative diseases, with emphasis on carrier design, delivery mechanisms, disease-specific applications, translational readiness, safety limitations, and future research priorities. Methods: A structured narrative literature search was conducted using PubMed, Google Scholar, ScienceDirect, SpringerLink, Web of Science, and open-access biomedical repositories. Search terms combined concepts related to the blood-brain barrier, nanotechnology, nanoparticles, liposomes, lipid nanoparticles, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, exosomes, receptor-mediated transcytosis, intranasal delivery, focused ultrasound, Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, neuroinflammation, and neurodegeneration. Eligible sources included mechanistic studies, in vitro blood-brain barrier models, animal studies, early clinical studies, disease-focused reviews, and clinically relevant drug-delivery literature. Findings were synthesized narratively because the evidence was heterogeneous in platform type, disease model, payload, route of administration, outcome measure, and translational stage. Results: The evidence indicates that nanocarriers can improve several delivery-related barriers by protecting unstable payloads, increasing apparent brain exposure, prolonging circulation, supporting ligand-mediated targeting, enabling controlled release, and reducing some off-target effects. Receptor-mediated transcytosis, lipid and polymeric nanoparticles, exosome-based delivery, intranasal nanoformulations, and focused ultrasound-assisted blood-brain barrier opening were the most frequently discussed strategies. Alzheimer disease and Parkinson disease had the most developed preclinical evidence base, whereas Huntington disease and amyotrophic lateral sclerosis were supported mainly by conceptual and early preclinical delivery frameworks. Focused ultrasound-mediated blood-brain barrier opening had the strongest early human translational evidence, particularly in Alzheimer disease. However, most nanoparticle and exosome-based therapies remain preclinical, and evidence linking brain uptake to target engagement, long-term safety, and meaningful clinical outcomes remains limited. Conclusion: Nanotechnology-based blood-brain barrier delivery is a promising but not yet clinically established approach for neurodegenerative diseases. Future studies must move beyond proof of brain uptake and demonstrate active payload release, cell-specific target engagement, repeated-dose safety, scalable manufacturing, disease-stage specificity, and patient-relevant clinical benefit.