What are the transport routes across the blood brain barrier?

October 12, 2025 •

3 min read

The blood-brain barrier (BBB) prevents entry of over 98% of small-molecule drugs and virtually all large-molecule therapeutics into the brain. Understanding what are the transport routes across the blood brain barrier is therefore critical for developing effective medications for central nervous system disorders.

Quick Summary

The blood-brain barrier regulates substance passage into the central nervous system through two primary routes, the transcellular and paracellular pathways. Mechanisms include passive diffusion for small, lipid-soluble molecules, carrier-mediated transport for essential nutrients, and transcytosis for larger molecules, counteracted by active efflux pumps.

Key Points

Endothelial Tight Junctions: The primary physical barrier of the BBB consists of tight junctions between endothelial cells that largely prevent paracellular transport of most molecules.
Lipid Solubility is Key for Passive Diffusion: Small, lipid-soluble molecules can cross the BBB passively, but most small-molecule drugs lack this property.
Carrier Proteins Transport Nutrients: Essential nutrients like glucose and amino acids cross the barrier via specific protein carriers, a process called carrier-mediated transport (CMT).
Transcytosis for Large Molecules: Large molecules like proteins and antibodies are transported via receptor-mediated (RMT) or adsorptive-mediated (AMT) transcytosis, which are energy-dependent vesicular processes.
Efflux Pumps Limit Drug Entry: Active efflux transporters, including P-glycoprotein, pump drugs out of the brain, further restricting drug accumulation in the CNS.
Innovative Delivery Strategies Circumvent the Barrier: Researchers are developing methods like focused ultrasound, nanoparticles, and molecular Trojan horses to overcome the BBB's impermeability.
Barrier Disruption Carries Risks: Transiently opening the BBB using osmotic or chemical agents increases drug uptake but can also allow harmful substances to enter the brain.

The Formidable Guard: An Overview of the Blood-Brain Barrier

The blood-brain barrier (BBB) is a highly selective interface separating the central nervous system (CNS) from the bloodstream. This complex structure of endothelial cells, basement membrane, pericytes, and astrocyte end-feet forms the lining of brain capillaries. These components work together to maintain brain homeostasis and protect against pathogens and toxins. Tight junctions between endothelial cells create a strong seal that restricts movement between cells, known as paracellular passage. While crucial for protection, this barrier significantly hinders the delivery of most drugs for brain diseases.

Unveiling the Primary Transport Routes

Substances cross the BBB via two main pathways: the paracellular route (between cells) and the transcellular route (through cells). The specific mechanism depends on the molecule's characteristics, such as size, charge, and lipid solubility.

The Transcellular Pathway: A Passage Through Cells

The transcellular pathway is the main route for molecules entering the brain, requiring passage through the endothelial cells. Key mechanisms include:

Passive Diffusion: Small (<400-600 Da), lipid-soluble molecules move across cell membranes down their concentration gradient. Alcohol and nicotine use this path.
Carrier-Mediated Transport (CMT): Specific protein carriers transport essential water-soluble nutrients, mainly from the $SLC$ superfamily. $GLUT1$ transports glucose, $LAT1$ transports amino acids like L-DOPA, and $MCT1$ transports lactate.
Receptor-Mediated Transcytosis (RMT): Larger molecules like peptides and proteins bind to specific receptors on endothelial cells for transport. Examples of receptors include transferrin, insulin, and low-density lipoprotein receptors. This route is used in drug delivery with "molecular Trojan horses".
Adsorptive-Mediated Transcytosis (AMT): Positively charged molecules bind to the negatively charged cell surface, triggering this non-specific vesicular transport. Cationic proteins, some peptides, and nanoparticles utilize this pathway.

The Paracellular Pathway: A Restricted Gap

Movement between endothelial cells is severely limited by tight junctions. Usually, only small, water-soluble solutes can pass. However, techniques like osmotic disruption can temporarily increase permeability for drug delivery.

The Role of Efflux Transporters

Active efflux transporters, like P-glycoprotein ($ABC$ family), pump many compounds, including drugs, back into the bloodstream. This significantly challenges drug delivery to the CNS.

Comparison of Major Transport Routes


Mechanism	Pathway	Energy Required	Substances	Key Features
Passive Diffusion	Transcellular	No	Small, lipid-soluble molecules (<400-600 Da)	Non-saturable, concentration-dependent
Carrier-Mediated Transport (CMT)	Transcellular	No (facilitated diffusion) / Yes (active transport)	Essential nutrients (e.g., glucose, amino acids)	Saturable, specific to substrate structure
Receptor-Mediated Transcytosis (RMT)	Transcellular	Yes	Large macromolecules (peptides, proteins, antibodies)	Initiated by specific receptor binding, saturable
Adsorptive-Mediated Transcytosis (AMT)	Transcellular	Yes	Cationic proteins and peptides	Triggered by electrostatic attraction, non-specific binding
Paracellular Transport	Paracellular	No (passive diffusion)	Small, water-soluble molecules	Restricted by tight junctions, low overall permeability

Emerging Strategies to Exploit BBB Transport

To deliver therapeutics across the BBB, researchers are developing strategies. These include attaching drugs to ligands that use RMT ({Link: Frontiers frontiersin.org}), temporarily opening the BBB with focused ultrasound (FUS), encapsulating drugs in nanoparticles targeting RMT or AMT, developing drugs or inhibitors to block efflux pumps, using osmotic or vasoactive agents to increase paracellular permeability, and exploring intranasal delivery.

Conclusion

Understanding the transport routes across the blood-brain barrier is crucial for pharmacology. The BBB's complex mechanisms, including passive diffusion, carrier-mediated transport, transcytosis, and efflux pumps, pose a significant obstacle for CNS drug delivery. However, research has illuminated these pathways, leading to innovative strategies to overcome the barrier. As our understanding and technology advance, delivering systemic drugs for neurological disorders is becoming more feasible.

Frequently Asked Questions

The primary role of the blood-brain barrier is to protect the brain by regulating the passage of substances from the bloodstream into the central nervous system, maintaining a stable and controlled environment for brain function.

Small, lipid-soluble drugs typically cross the blood-brain barrier through passive diffusion, moving directly through the lipid bilayer of the endothelial cells down their concentration gradient.

Carrier-mediated transport (CMT) is a mechanism using specialized protein carriers, such as $GLUT1$ and $LAT1$, to transport essential, water-soluble nutrients like glucose and amino acids into the brain.

Researchers can utilize RMT for drug delivery by creating "molecular Trojan horses," where therapeutic agents are attached to ligands that specifically bind to and are transported by RMT receptors, like the transferrin receptor, on the BBB.

Efflux pumps, such as P-glycoprotein, are a major challenge because they actively transport a broad range of compounds, including many drugs, out of the brain endothelial cells, limiting the concentration of drugs that can accumulate in the brain.

Adsorptive-mediated transcytosis (AMT) is a vesicular transport mechanism initiated by the electrostatic attraction between positively charged molecules and the negatively charged surface of the endothelial cell membrane at the BBB.

Focused ultrasound (FUS) is a non-invasive technique that uses targeted ultrasound waves combined with intravenously injected microbubbles to temporarily and reversibly increase the permeability of the BBB, allowing for enhanced delivery of therapeutic agents to specific brain regions.