The blood-brain barrier (BBB) is a highly selective, semi-permeable membrane that protects the central nervous system (CNS) from harmful substances in the bloodstream, such as pathogens and toxins.
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While this protects the brain from external threats, it also presents a major challenge for treating neurological diseases, as many potentially therapeutic compounds are unable to cross.
One potential solution is using nanoparticles to deliver drugs across the BBB. Advances in nanotechnology have shown that nanoparticles can cross this barrier, opening new possibilities for treating brain disorders.1
How the BBB Works
The BBB is made up of endothelial cells, astrocytes, pericytes, tight junctions, and adherens junctions.
Endothelial cells form the core, lining the cerebral blood vessels and sealing them with specialized junctions. Unlike peripheral endothelial cells, those in the BBB lack fenestrations and contain many mitochondria, reflecting their role in energy-dependent transport.
Astrocytes and pericytes surround these cells, providing structural and functional support. Astrocytes regulate blood flow and ion balance, while pericytes maintain vascular stability and influence BBB permeability.1,2
The BBB protects the brain by physically blocking harmful substances, including toxins and immune cells. It also regulates the exchange of ions like sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) through specialized transporters. This balance is essential for neural signaling and synaptic function.
The BBB facilitates the controlled transport of nutrients, metabolites, and essential molecules while blocking unnecessary or harmful compounds.3 Small, lipid-soluble molecules, oxygen, glucose, and amino acids can cross the BBB through specific transport mechanisms. However, large, hydrophilic molecules and most drugs are blocked.
Transporters such as solute carriers and ATP-binding cassette (ABC) proteins regulate molecular exchange, ensuring that only necessary compounds reach neural tissue. When the BBB is disrupted or dysfunctional, it can contribute to neurological disease, making it a central target for CNS drug delivery.4
How Nanoparticles Cross the BBB
Several strategies have been developed to help nanoparticles cross the blood-brain barrier and improve drug delivery to the brain. Each mechanism offers a different route for transporting therapeutic agents into the CNS.
Passive Diffusion
Passive diffusion allows certain nanoparticles to cross the BBB without relying on active transport. This is most effective with lipid-based nanoparticles, which can interact with the lipid bilayer of endothelial cells and move through the transcellular pathway.
For example, lipophilic nanoparticles such as HSPC:CHOL:DSPE-PEG2000 can partition into the cell membrane and pass through the barrier.5
Targeting ligands can further improve penetration. OX26 antibody-modified PEGylated cationic lipid nanoparticles (OX26-PEG-CSLN), for instance, have demonstrated enhanced drug delivery and extended retention in the brain, making them a promising option for CNS therapies.6
Receptor-Mediated Transport
In receptor-mediated transport, nanoparticles cross the BBB by binding to specific receptors on endothelial cells. This active mechanism enables targeted entry into the brain.
Polymeric nanoparticles, such as PLGA-based (Poly(lactic-co-glycolic acid)) carriers, are often functionalized with targeting ligands like transferrin, insulin, or low-density lipoprotein receptors to enhance BBB penetration.
Thanks to their adaptable surface chemistry, gold nanoparticles can also be engineered with receptor-specific ligands, making them especially useful for targeted drug delivery.7
Adsorptive-Mediated Transport
In adsorptive-mediated transport, charged nanoparticles use electrostatic interactions to cross the BBB. Cationic nanoparticles, such as PEGylated lipids and certain polymer-based systems, bind to the negatively charged membranes of brain endothelial cells. This interaction promotes endocytosis and facilitates nanoparticle entry into the brain.
This method allows for improved drug delivery to the CNS and has been explored for various neurological disease treatments.8
Temporary BBB Disruption
Temporarily disrupting the BBB is another strategy for enhancing nanoparticle delivery to the brain. Magnetic nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs), are used in combination with focused ultrasound to transiently open the tight junctions of the barrier.
This technique relies on microbubble-enhanced ultrasound to generate mechanical forces that increase BBB permeability, allowing therapeutic agents to reach brain tissue. The controlled nature of this approach minimizes potential damage while improving drug delivery efficiency.9
Applications in Treatment: Case Studies
Nanoparticles have shown significant potential in treating neurological disorders by improving drug delivery to the brain. Key applications include:
Neurodegenerative Diseases
The restrictive nature of the BBB makes treating diseases like Alzheimer’s and Parkinson’s difficult. To overcome this, researchers have developed nanoparticle-based delivery systems.
For example, Wang et al. designed polymeric nanoparticles conjugated with amyloid-β-derived peptides to target Alzheimer’s pathology. This approach improved drug accumulation in affected brain regions.10
Similarly, Zhang et al. demonstrated that liposomes functionalized with transferrin receptor aptamers enhanced BBB penetration. This enabled the delivery of acetylcholinesterase reactivators, which are crucial in managing neurodegeneration.11
Dr Andrew Care and Miss India Boyton | Using nanotechnology to fight Alzheimer’s disease
Brain Tumors
Treating brain tumors, especially glioblastoma, requires dual-functional drug delivery systems that can both cross the BBB and target tumor cells. Liposomes have been modified with tumor-penetrating peptides and antibodies to improve localization in glioblastoma.
For example, Di Shi et al. demonstrated a system incorporating SPIONs and doxorubicin that enabled thermo-responsive drug release under an alternating magnetic field, effectively enhancing chemotherapy efficacy.12
In other research by Singh et al., functionalized polymeric nanoparticles with glioma-targeting ligands were shown to enhance drug retention and accumulation in brain tumors.13
Targeted Drug Delivery
Recent advancements in biomimetic and polymeric delivery systems have significantly improved targeted therapies for brain disorders. PEGylated liposomes, exosome-like nanoparticles, and polymeric micelles have all been designed to selectively transport therapeutic agents across the BBB.
For example, Lee et al. reported that cell membrane-coated nanoparticles were developed to improve BBB penetration and increase drug accumulation in the brain.14
Similarly, Liu et al. demonstrated that iron oxide nanoparticles conjugated with targeting ligands can co-deliver RNA-based therapeutics and chemotherapeutic drugs, supporting gene-chemotherapy approaches.15
Challenges and Future Perspectives
Despite their potential, nanoparticle-based drug delivery systems face several key challenges. One concern is neurotoxicity. Some nanoparticles can activate microglia, leading to oxidative stress and neuronal damage. Metallic nanoparticles like silica and iron oxide may also accumulate in brain tissue, raising concerns about long-term toxicity.
Increasing BBB permeability may unintentionally allow harmful substances to enter the brain. To reduce risks, careful optimization of nanoparticle composition, dosage, and surface modifications is essential.1,2
Another hurdle is rapid clearance by the reticuloendothelial system (RES), which limits brain bioavailability. Opsonization by plasma proteins can further accelerate clearance. Factors such as particle size, surface charge, and PEGylation must be fine-tuned to improve circulation time and BBB penetration.1,2
Clinical translation also faces regulatory barriers. Extensive safety testing and standardized evaluation protocols are required. In addition, large-scale manufacturing and consistency across batches remain ongoing challenges.
Future research must focus on developing robust preclinical models and clear regulatory frameworks to support the safe and effective use of nanoparticles in treating brain disorders.
For more information on nanoparticle-based drug delivery and targeting strategies, explore the following resources:
References and Further Readings
1. Wu, D.; Chen, Q.; Chen, X.; Han, F.; Chen, Z.; Wang, Y., The Blood–Brain Barrier: Structure, Regulation and Drug Delivery. Signal transduction and targeted therapy 2023, 8, 217. https://www.nature.com/articles/s41392-023-01481-w
2. Teleanu, D. M.; Chircov, C.; Grumezescu, A. M.; Volceanov, A.; Teleanu, R. I., Blood-Brain Delivery Methods Using Nanotechnology. Pharmaceutics 2018, 10, 269. https://pubmed.ncbi.nlm.nih.gov/30544966/
3. Yang, X.; Wang, Q.; Cao, E., Structure of the Human Cation–Chloride Cotransporter Nkcc1 Determined by Single-Particle Electron Cryo-Microscopy. Nature Communications 2020, 11, 1016. https://pubmed.ncbi.nlm.nih.gov/32081947/
4. Hersh, A. M.; Alomari, S.; Tyler, B. M., Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology. International journal of molecular sciences 2022, 23, 4153. https://pubmed.ncbi.nlm.nih.gov/35456971/
5. Hladky, S. B.; Barrand, M. A., Elimination of Substances from the Brain Parenchyma: Efflux Via Perivascular Pathways and Via the Blood–Brain Barrier. Fluids and Barriers of the CNS 2018, 15, 1-73. https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-018-0113-6
6. Liu, Z.; Zhang, L.; He, Q.; Liu, X.; Ikechukwu, O. C.; Tong, L.; Guo, L.; Yang, H.; Zhang, Q.; Zhao, H., Effect of Baicalin-Loaded Pegylated Cationic Solid Lipid Nanoparticles Modified by Ox26 Antibody on Regulating the Levels of Baicalin and Amino Acids During Cerebral Ischemia–Reperfusion in Rats. International journal of pharmaceutics 2015, 489, 131-138. https://pubmed.ncbi.nlm.nih.gov/25895718/
7. Prabhu, S.; Goda, J. S.; Mutalik, S.; Mohanty, B. S.; Chaudhari, P.; Rai, S.; Udupa, N.; Rao, B. S. S., A Polymeric Temozolomide Nanocomposite against Orthotopic Glioblastoma Xenograft: Tumor-Specific Homing Directed by Nestin. Nanoscale 2017, 9, 10919-10932. https://pubs.rsc.org/en/content/articlelanding/2017/nr/c7nr00305f
8. Choudhari, M.; Hejmady, S.; Saha, R. N.; Damle, S.; Singhvi, G.; Alexander, A.; Kesharwani, P.; Dubey, S. K., Evolving New-Age Strategies to Transport Therapeutics across the Blood-Brain-Barrier. International Journal of Pharmaceutics 2021, 599, 120351. https://pubmed.ncbi.nlm.nih.gov/33545286/
9. Gorick, C. M.; Breza, V. R.; Nowak, K. M.; Cheng, V. W.; Fisher, D. G.; Debski, A. C.; Hoch, M. R.; Demir, Z. E.; Tran, N. M.; Schwartz, M. R., Applications of Focused Ultrasound-Mediated Blood-Brain Barrier Opening. Advanced drug delivery reviews 2022, 191, 114583. https://pubmed.ncbi.nlm.nih.gov/36272635/
10. Wang, K.; Wang, L.; Chen, L.; Peng, C.; Luo, B.; Mo, J.; Chen, W., Intranasal Administration of Dauricine Loaded on Graphene Oxide: Multi-Target Therapy for Alzheimer’s Disease. Drug Delivery 2021, 28, 580-593. https://pubmed.ncbi.nlm.nih.gov/33729067/
11. Zhang, Y.; He, J.; Shen, L.; Wang, T.; Yang, J.; Li, Y.; Wang, Y.; Quan, D., Brain-Targeted Delivery of Obidoxime, Using Aptamer-Modified Liposomes, for Detoxification of Organophosphorus Compounds. Journal of controlled release 2021, 329, 1117-1128. https://pubmed.ncbi.nlm.nih.gov/33096123/
12. Shi, D.; Mi, G.; Shen, Y.; Webster, T. J., Glioma-Targeted Dual Functionalized Thermosensitive Ferri-Liposomes for Drug Delivery through an in Vitro Blood–Brain Barrier. Nanoscale 2019, 11, 15057-15071. https://pubs.rsc.org/en/content/articlelanding/2019/nr/c9nr03931g
13. Lakkadwala, S.; dos Santos Rodrigues, B.; Sun, C.; Singh, J., Dual Functionalized Liposomes for Efficient Co-Delivery of Anti-Cancer Chemotherapeutics for the Treatment of Glioblastoma. Journal of Controlled Release 2019, 307, 247-260. https://pmc.ncbi.nlm.nih.gov/articles/PMC6732022/
14. Lee, J. Y.; Vyas, C. K.; Kim, G. G.; Choi, P. S.; Hur, M. G.; Yang, S. D.; Kong, Y. B.; Lee, E. J.; Park, J. H., Red Blood Cell Membrane Bioengineered Zr-89 Labelled Hollow Mesoporous Silica Nanosphere for Overcoming Phagocytosis. Scientific reports 2019, 9, 7419. https://pubmed.ncbi.nlm.nih.gov/31092899/
15. Liu, F.; Wu, H.; Peng, B.; Zhang, S.; Ma, J.; Deng, G.; Zou, P.; Liu, J.; Chen, A. T.; Li, D., Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia–Chemotherapy Combination for Brain Cancer Treatment. Nano Letters 2021, 21, 8111-8118. https://pubmed.ncbi.nlm.nih.gov/34597054/
