Crossing the Blood-Brain Barrier with the Trojan Horse Delivery System

Neurological disorders place a huge burden on public health, affecting billions of people globally. However, multiple pharmaceutical companies are reducing their investment in neurology, with AstraZeneca completely closing this department in 2025. Unfortunately, a high percentage of neurological drugs fail clinical trials, largely due to the difficulty of delivering drugs to the brain through the blood-brain barrier (BBB).

What is the blood-brain barrier and how does it prevent drug delivery?

The BBB describes the unique properties of the vasculature lining the CNS, acting as a physiological barrier that tightly regulates the movement of molecules. While this is important for neuronal function and homeostasis, it restricts the delivery and efficacy of neurological drugs.

The endothelial cells lining the BBB are joined by tight junctions, which reduce the movement of larger molecules across membranes (transcytosis) and prevent smaller molecules crossing membranes between gaps in cells (paracellular flux). Some small lipid-soluble molecules are able to diffuse into the brain; however, the BBB contains efflux transporters that pump these molecules back out. Therefore, even if drugs are able to reach the brain, they may not remain or accumulate, resulting in limited efficacy.

Bypassing the blood-brain barrier to allow drug delivery

Given these difficulties, new research is investigating ways of bypassing the BBB and allowing drug entry into the CNS. One such solution is targeting specific nutrient transporters in the BBB which could potentially be exploited to allow drugs to enter the brain. For example, small neurological drugs can be made structurally similar to a substrate normally transported by the BBB’s carrier proteins and are thus transported into the brain by the carrier protein. This technique is used in the anti-Parkinsonian drug levodopa, which is structurally similar to phenylalanine, so is transported into the brain by the L-type amino acid transporter.

"Even if drugs are able to reach the brain, they may not remain or accumulate, resulting in limited efficacy."

However, this method is not feasible for larger molecules. Instead, a method called the Trojan Horse delivery system may allow larger drugs to enter the CNS. This involves coupling the drug with a ligand that is specific to a receptor on the BBB membrane. The drug-ligand complex is then packaged into a drug transporter composed of nanosized particles, called a nanocarrier. These techniques are very innovative as instead of trying to oppose the BBB, they exploit the BBB to transport the drug.

The predominant advantage of the Trojan Horse delivery system is the increased efficiency of drug delivery. Another strength is that theoretically, the drugs can be delivered to particular sites, as the drug is coupled to a receptor-specific ligand and thus  the drug is transported to that specific site. However, the Trojan Horse delivery system is still being researched and there are several factors that may limit its capabilities. For example, nanocarriers may trigger immune responses and toxicity. Also, in practice, targeted drug delivery is limited, causing the drugs to potentially accumulate in healthy CNS tissue and cause unwanted side effects.

Trojan Horse delivery systems and Alzheimer's Disease

Trojan horse delivery systems have been tested with drugs for Alzheimer’s Disease. Oxidative stress is considered to be a driver of Alzheimer’s, so Bai et al (2023) tested a Trojan Horse delivery system to reduce the oxidative stress in the brain and reduce symptoms in mice. They used extracellular vesicles (mimicking nanocarriers) which contained an antioxidant called resveratrol and platinum nanoparticles, which mimic protective enzymes. These vesicles were coated with a peptide found on the rabies virus, allowing them to target brain tissue. Their results showed that the vesicles were able to cross the BBB, reduce oxidative stress, and even reduce memory loss. This study suggests that the Trojan Horse delivery system does indeed increase drug delivery into the brain and could be effective in future drug development.

" [The Trojan Horse delivery system] involves coupling the drug with a ligand that is specific to a receptor on the BBB membrane."

Looking to the future

The Trojan Horse delivery system may be a promising new technique in neurological drug development as it seems to overcome the challenges posed by the BBB. Further research is required to increase specificity of drug delivery and reduce immune rejection, but this method may offer hope to the billions suffering with neurological disease.

References:

1. Rushendran R, Begum RF, Singh SA, Narayanan PL, Vellapandian C, Prajapati BG, et al. Navigating neurological disorders: harnessing the power of natural compounds for innovative therapeutic breakthroughs. Excli j. 2024;23:534–69.

2. Zaragoza Domingo S, Alonso J, Ferrer M, Acosta MT, Alphs L, Annas P, et al. Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials. European Neuropsychopharmacology. 2024;83:32–42.

3. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1):a020412.

4. Porro G, Basile M, Xie Z, Tuveri GM, Battaglia G, Lopes CDF. A new era in brain drug delivery: Integrating multivalency and computational optimisation for blood–brain barrier permeation. Advanced Drug Delivery Reviews. 2025;224:115637.

5. Lei K, Zhou L, Dan M, Yang F, Jian T, Xin J, et al. Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting. Pharmaceutics [Internet]. 2025; 17(3):[280 p.].

6. Bai Z, Ge K, Fu J, Yu D, Hua Z, Xue S, et al. Engineered urinary-derived extracellular vesicles loaded nanoenzymes as Trojan horses to regulate the inflammatory microenvironment for treatment of Alzheimer's disease. Chemical Engineering Journal. 2023;465:142955.

   
   

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This article was written by Alisha Hussain and edited by Julia Dabrowska, with graphics produced by Lilly Green. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.