The central nervous system (NS), made up of the brain and spinal cord, is responsible for processing and integrating information, and it controls most functions of the body and mind, including movement, sensation, thought, and emotion. Common disorders of the CNS can be vascular, infectious, structural, functional, degenerative or psychiatric and although there are marketed and emerging drugs that treat or slow the progression of some of these conditions, reaching the targeted areas within the CNS remains a highly complex topic. This is due to numerous challenges such as the blood-brain-barrier (BBB). However, emerging innovations aim to overcome these barriers and enable safe treatment of the brain. In this article, Alcimed explores the barriers to drug delivery to the brain and the approaches currently used to deliver therapies to the central nervous system.
The brain is protected by multiple barriers, including the blood-cerebrospinal fluid barrier and the more well-known BBB. The BBB prevents pathogens, solutes and most molecules from non-selectively crossing from the bloodstream into the brain…but it also stops neurotherapeutics: it has been estimated that it prevents more than 98% of these potential drugs from entering the brain.1Wu, D., Chen, Q., Chen, X., Han, F., Chen, Z., & Wang, Y. (2023). The blood–brain barrier: Structure, regulation and drug delivery. Signal Transduction and Targeted Therapy, 8(1), 217. https://doi.org/10.1038/s41392-023-01481-w Generally, the BBB allows passive diffusion of small, lipid-soluble molecules, typically with a molecular weight below 400–600 Da, which constrains the types of drugs that can be developed for brain disorders. However, molecular size is only part of the story. The BBB also contains a range of highly selective, saturable transport systems (including carrier-mediated and receptor-mediated transport pathways) that actively regulate the movement of essential nutrients, peptides and other molecules into the brain. These transport mechanisms are increasingly being harnessed by drug developers to deliver larger therapeutic molecules, such as biologics, across the BBB.
Structurally, the BBB is formed by tightly packed endothelial cells that line the walls of brain blood vessels. These endothelial cells are connected by tight junctions and express specialized BBB proteins that tightly regulate the entry and exit of molecules. Other cell types, including pericytes, astrocytes and neurons, also contribute to the structure and function of the BBB.
While it’s known that the BBB can become “leaky” in certain disease environments, such as around brain tumors, the exact mechanisms of how and when this happens are still being unravelled, and even our knowledge of the mechanisms involved in a healthy BBB is still incomplete.
On top of the BBB, efflux pumps, proteins that act like microscopic bouncers, actively remove foreign substances from brain cells, including many therapeutic compounds. As a result, these drugs can be pumped out of the brain back into the blood before they have time to work.
Finally, most early-stage research relies on animal models, which don’t always reflect what happens in humans. For example, a drug that travels easily along a mouse’s short spinal cord may fail to reach the human brain due to the much longer distance. Moreover, many of these studies are performed in healthy or genetically modified animals with an intact BBB, so researchers have limited insight into how their treatments will behave in a diseased brain and/or with an impaired BBB.
The BBB is a huge challenge for brain drug delivery but there are many others such as a limited understanding of the healthy and unhealthy brain, issues with clinical trials, immunogenicity challenges and social and economic hurdles.
Despite major scientific advances, the brain remains one of the most complex and least understood organs in the human body. Our limited understanding of how the healthy brain works, and how it changes with disease, continues to challenge researchers. While we’re learning more every day, vast gaps in knowledge remain, especially when it comes to the many brain disorders that affect individuals in unique ways. These variations layer complexity upon complexity.
Clinical trials bring their own set of challenges. Ethical considerations are critical, should a terminally ill patient receive a placebo in a control group, for example? Recruiting patients and properly stratifying them is another major hurdle, prompting the push for new biomarkers, with some promising new blood tests in Alzheimer’s disease for example.
Safety is another concern. Some procedures used to deliver drugs to the brain are highly invasive, and even non-invasive treatments can cause side effects elsewhere in the body.
The potential for treatments to trigger immune reactions, is also a major challenge. For example, while nanoparticles are being explored as drug carriers, they can provoke strong immune responses. Some very early research is looking at using red blood cells or immune cells themselves as drug delivery vehicles.
Beyond the scientific and clinical challenges, there are important social and economic challenges to consider. Equity in access is a growing concern, with new therapies that could be extremely expensive. It is therefore worth thinking ahead to how we can make these life changing drugs available to all those that need them.
High development costs and low success rates contribute to this potential high price point. CNS drugs have a lower FDA approval rate (~6%) compared to other therapeutic areas (~13%), and they typically take longer to reach the market.2Gribkoff, V. K., & Kaczmarek, L. K. (2016). The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology, 120, 11–19. https://doi.org/10.1016/j.neuropharm.2016.03.021
Finally, social stigma, poor awareness, slow diagnosis, and public hesitation around brain surgery or unconventional treatments are also challenges to adoption.
Despite these many challenges, the field of CNS therapeutics is vibrant and rapidly evolving. Major pharmaceutical companies and startups alike are investing in innovative approaches, leading to exciting partnerships, acquisitions, and recent regulatory approvals, such as the new Alzheimer’s monoclonal antibodies. One example of a promising development is Roche’s BrainShuttle™ platform, designed to enhance drug delivery across the BBB. Combined with trontinemab, a monoclonal antibody, this technology is in phase III (as of late 2025). Another example is Denali Therapeutics’ Transport Vehicle (TV) platform, which also exploits receptor-mediated transcytosis (a selective transport system) to shuttle biologics across the BBB and has advanced multiple clinical candidates for lysosomal storage disorders and neurodegenerative diseases. These advances marks a hopeful step forward in the quest to overcome the unique challenges of treating the brain.
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Today, CNS drugs are delivered in many ways. For some serious conditions such as glioma, highly invasive procedures are accepted but for many indications none of the delivery methods are ideal as the efficacy versus invasiveness balance is in most cases insufficient. However, this risk–benefit equation is evolving with the emergence of long-lasting and potentially disease-modifying therapies. For example, gene therapies, which may provide durable clinical benefit after a single administration, could justify more invasive delivery approaches. Additionally, a lot of the drugs available today are small molecules that can passively diffuse into the brain, but the growing interest in using biologics has pushed the challenge of overcoming the BBB back to the forefront of peoples’ minds. For example, the recent development of monoclonal antibody therapies for Alzheimer’s that need to be administered frequently at high doses has prompted the desire for better delivery technologies.
There are two main approaches to drug delivery: direct or systemic delivery.
In direct delivery, the drug enters the CNS directly to avoid entering the bloodstream and having to cross the BBB, and limits whole body exposure and related side effects. This is the case for intrathecal delivery (injection of the drug into the cerebrospinal fluid), intraparenchymal delivery (injection of the drug directly into the brain) and the nose to brain route, a new and still immature alternative delivery route.
In systemic delivery, the drug enters the bloodstream to reach the brain. All organs are therefore exposed to the drug as it flows freely throughout the body. The two main challenges for this type of delivery are to cross the BBB successfully and to limit systemic exposure induced side effects. Approaches such as receptor mediated transcytosis and low intensity focused ultrasounds are aiming to overcome these challenges.
Delivering drugs to the brain remains one of the most complex challenges in modern medicine due to the protective but restrictive nature of the BBB. While traditional delivery methods fall short, recent innovations are showing real promise. Both direct and systemic approaches represent significant strides in overcoming these barriers. As biologics and precision therapies gain traction, the urgency to refine CNS delivery systems has intensified. Continued innovation, supported by advances in molecular engineering and clinical validation, offers renewed hope that we are moving closer to safely and effectively treating the brain. Alcimed closely follows the rapid developments of these technologies that are revolutionizing tomorrow’s healthcare and is ready to support you on these topics. Don’t hesitate to contact our team!
About the author,
Elia, Consultant in Alcimed’s Healthcare team in France
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