Abstract
Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions.
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Acknowledgements
The authors thank all authors whose work in CNS drug delivery and related areas contributed to this Review. The authors also thank the reviewers for their constructive suggestions, which helped them to improve this Review.
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All authors researched data for the article. J.G., Z.J.X., S.G., J.M.K. and N.J. contributed substantially to the discussion of the content. J.G., Z.J.X., S.G. and C.J. wrote the article. C.J. crafted all the figures. All authors reviewed and/or edited the manuscript before submission.
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N.J. and J.M.K. have one pending patent on nanoparticles for gene delivery in the brain. The other authors declare no competing interests.
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Nature Reviews Materials thanks Horacio Cabral and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Related links
Basal Ganglia: https://my.clevelandclinic.org/health/body/23962-basal-ganglia
Cognitive functioning: https://mayfieldclinic.com/pe-pd.htm
Glossary
- Blood–brain barrier
-
(BBB). A selective barrier formed by endothelial cells, astrocytes and pericytes that regulates the passage of substances from the bloodstream into the central nervous system.
- Braak stages
-
A classification system that describes the progression of abnormal protein deposits, particularly tau proteins, within specific brain regions, providing insights in pathology progression in neurodegenerative diseases such as Alzheimer disease.
- Cerebrospinal fluid
-
Produced by the choroid plexus in brain ventricles; it surrounds the brain and spinal cord, providing mechanical support, nutrient delivery, waste removal and regulation of intracranial pressure within the central nervous system.
- Convection-enhanced delivery
-
A local delivery method that utilize pressure to drive the flow of therapeutic agents through the brain parenchyma.
- Extracellular matrix
-
A dynamic network of proteins and carbohydrates in the brain that surround neurons and glial cells, influencing synaptic plasticity, cell adhesion and neuronal migration.
- Glymphatic pathway
-
A waste clearance system unique to the brain that relies on glial cells (especially astrocytes) to facilitate the cerebrospinal fluid–interstitial fluid exchange in the perivascular space.
- Interstitial fluid
-
A fluid that fills the brain interstitial space and directly surrounds neurons and glial cells for nutrient delivery, waste removal and cell signalling.
- Parenchyma
-
The main functional tissue of the brain, consisting of neurons, glial cells and other acellular supporting structures to maintain the cognitive and physiological function of the brain.
- Protein corona
-
A layer of proteins that adsorb onto the surface of nanoparticles upon exposure to biological fluids, influencing their behaviour, interactions and biological responses.
- Reticuloendothelial system
-
(RES). A network of phagocytic cells, mainly macrophages, that are primarily located in the liver and spleen and actively remove foreign substances via engulfment.
- Tight junctions
-
Specialized intercellular junctions between endothelial cells that create a barrier to control the passage of ions, molecules and cells across epithelial and endothelial cell layers.
- Transcytosis
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The process by which macromolecules or particles are transported across a cell, involving their uptake on one side through endocytosis, intracellular transport, and release on the opposite side through exocytosis.
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Gao, J., Xia, Z.(., Gunasekar, S. et al. Precision drug delivery to the central nervous system using engineered nanoparticles. Nat Rev Mater (2024). https://doi.org/10.1038/s41578-024-00695-w
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DOI: https://doi.org/10.1038/s41578-024-00695-w
