How Do Things Get Through the Blood-Brain Barrier?

October 12, 2025 •

3 min read

Over 98% of small-molecule drugs and nearly all large-molecule biotherapeutics cannot cross the blood-brain barrier (BBB). This biological shield makes figuring out how do things get through the blood-brain barrier a central challenge for treating central nervous system disorders.

Quick Summary

The blood-brain barrier is a cellular defense system controlling brain access. Molecules cross it through passive diffusion, carrier-mediated transport, and transcytosis, while drug delivery methods often exploit or temporarily disrupt these systems.

Key Points

Passive Diffusion: Small, fat-soluble molecules pass directly through the lipid membranes of brain endothelial cells.
Carrier-Mediated Transport (CMT): Essential nutrients like glucose and amino acids are ferried across the barrier by specific protein transporters.
Receptor-Mediated Transcytosis (RMT): Large molecules, such as proteins, are delivered via a 'Trojan horse' mechanism by binding to specific receptors and being engulfed in vesicles.
Active Efflux: P-glycoprotein and other pumps actively transport many drugs out of the brain, hindering their effectiveness.
Targeted Nanoparticles: Researchers use engineered nanoparticles (liposomes, polymeric) to encapsulate drugs and target specific receptors for enhanced delivery.
Focused Ultrasound (FUS): This non-invasive technique temporarily and reversibly opens the BBB in targeted regions, allowing drugs to enter.

The blood-brain barrier (BBB) is a dynamic and highly selective boundary that separates the brain's circulating blood from the brain's extracellular fluid. This crucial defense mechanism is composed of specialized endothelial cells lining CNS capillaries, which are connected by tight junctions that restrict solute passage. The neurovascular unit, which includes pericytes and astrocyte endfeet, also contributes to regulating substance entry. The BBB protects the brain from harmful substances while allowing essential nutrients to pass in a controlled manner. However, this barrier significantly impedes the delivery of many potential CNS drugs.

Permeability Mechanisms: How Molecules Cross the BBB

Several mechanisms are employed by the BBB to regulate the entry of molecules into the brain.

Passive Diffusion

Small, lipid-soluble molecules can cross the lipid bilayer of endothelial cell membranes down a concentration gradient. The rate of passage depends on their lipid solubility and molecular weight. Examples include ethanol, nicotine, and many sedatives.

Carrier-Mediated Transport (CMT)

Essential nutrients like glucose and amino acids use specific protein transporters. This saturable process can be leveraged for drug delivery. Influx transporters, like GLUT1 for glucose and LAT1 for amino acids, move substances into the brain. Efflux transporters, such as P-glycoprotein (P-gp) from the ABC family, actively pump substances back into the blood, limiting brain drug concentrations.

Receptor-Mediated Transcytosis (RMT)

Larger molecules like proteins and antibodies can enter via RMT, a vesicular pathway. This process involves a ligand binding to a specific receptor on the endothelial cell, internalization of the complex in a vesicle, sorting of cargo and receptor within endosomes, and exocytosis of the cargo into the brain.

Adsorptive-Mediated Transcytosis (AMT)

AMT is a less specific vesicular transport triggered by electrostatic attraction between positively charged substances and the negatively charged cell membrane surface. Some cationic peptides and proteins utilize this pathway.

Modern Strategies for Targeted Delivery

Overcoming the BBB's defenses requires innovative drug delivery methods.

Nanoparticle-Based Systems

Nanoparticles, such as liposomes and polymeric nanoparticles, can carry drugs across the BBB. They can be designed to encapsulate drug payloads and have surfaces modified with ligands for enhanced targeting. Nanoparticles offer advantages like controlled release and payload protection and primarily cross via transcytosis or by temporarily loosening tight junctions.

Trojan Horse Strategy with Antibodies

This strategy adapts the RMT pathway. An antibody targeting an RMT receptor, like the transferrin receptor (TfR), is fused to a therapeutic molecule. This fusion protein is then transported across the BBB via the TfR-mediated transcytosis pathway.

Focused Ultrasound (FUS) with Microbubbles

FUS is a non-invasive technique that can temporarily open the BBB in a localized area. Microbubbles are injected and ultrasound waves are applied to a specific brain region. The oscillating microbubbles mechanically stress the endothelial cells, disrupting tight junctions and allowing systemic therapeutics to enter the targeted area.

Comparison of BBB Drug Delivery Strategies

Selecting the appropriate strategy for CNS therapies requires understanding their mechanisms, advantages, and disadvantages.


Strategy	Mechanism	Advantages	Disadvantages
Passive Diffusion	Molecule passes through endothelial cell membranes based on its physicochemical properties.	Simple; requires no energy.	Limited to small, lipid-soluble molecules. Often countered by efflux pumps.
Carrier-Mediated Transport	Uses endogenous protein transporters for specific nutrients.	Exploits natural, physiological pathways.	Limited to molecules structurally similar to natural ligands; can be saturated.
Receptor-Mediated Transcytosis	Engulfs receptor-bound molecules in vesicles for transport across the cell.	Highly specific for large molecules like antibodies.	High binding affinity can lead to lysosomal degradation; complex to engineer.
Nanoparticle Delivery	Delivers drug encapsulated in a carrier (e.g., liposome).	Controlled release; can target specific cells; protects cargo.	Potential toxicity; requires regulatory approval; expensive; low targeting efficiency can be an issue.
Focused Ultrasound (FUS)	Mechanically disrupts tight junctions with oscillating microbubbles.	Non-invasive; spatially precise targeting; repeatable.	Temporary effect (hours); requires specialized equipment; potential for off-target effects.
BBB Disruption (Osmotic)	Temporarily opens tight junctions by shrinking endothelial cells with hyperosmolar agents.	Can deliver drugs to larger brain regions.	Invasive (intra-arterial injection); nonspecific; risk of side effects like cerebral edema or seizures.

Conclusion

Overcoming the blood-brain barrier is a significant challenge in pharmacology. However, research into leveraging the brain's natural transport systems, developing nanoparticle carriers, and utilizing localized disruption techniques is providing promising new avenues. A personalized approach that matches the delivery strategy to the specific disease, drug properties, and patient needs is likely the future of CNS therapeutics. Continued exploration of the BBB's complexities is essential for developing effective treatments for neurological diseases.

Frequently Asked Questions

The BBB is a highly selective semipermeable border of specialized endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the brain extracellular fluid. It protects the brain from pathogens and toxins while regulating the entry of essential nutrients.

Drugs face multiple hurdles, including tight junctions between endothelial cells that block passage, a layer of efflux pumps that actively expel many substances, and the need for specific transport mechanisms for anything other than small, lipid-soluble molecules.

Many psychoactive drugs, including some antidepressants, are small and sufficiently lipid-soluble to cross the blood-brain barrier via passive diffusion, moving directly through the endothelial cell membranes.

Yes, nanoparticles like liposomes and polymeric nanoparticles can be engineered to cross the BBB, often with surface modifications that target specific receptors to facilitate entry via transcytosis.

This strategy involves attaching a drug or nanoparticle to a ligand, such as an antibody, that binds to a receptor on the BBB endothelium. This tricks the cell into internalizing the complex and transporting it across via transcytosis.

Yes, techniques like Focused Ultrasound (FUS) combined with microbubbles can temporarily and reversibly disrupt the tight junctions, allowing systemic drugs to enter a targeted brain region.

Efflux pumps, like P-glycoprotein, actively transport many drugs from the brain endothelium back into the bloodstream, significantly reducing the drug's concentration in the brain. Researchers must design drugs to bypass or inhibit these pumps.