Nanoparticle-Mediated Drug Delivery Across the Blood-Brain Barrier

The blood–brain barrier (BBB) is a highly selective endothelial interface that safeguards the central nervous system but simultaneously impedes the delivery of most pharmacological agents. Nanoparticle-mediated drug delivery offers a versatile toolkit to overcome this obstacle by engineering carriers in the 1–100 nm range with tailored physicochemical properties. Strategies to traverse the BBB include passive diffusion of ultrasmall carriers, ligand-directed receptor-mediated transcytosis, cell-penetrating peptide conjugation and stimuli-responsive disruption of tight junctions. Surface functionalisation with targeting moieties such as peptides, antibodies or sugars enhances selectivity for brain endothelium while minimising off-target uptake. Physical approaches, notably focused ultrasound, can transiently widen paracellular gaps to boost nanoparticle extravasation. Engineered nanocarriers range from liposomes, polymeric micelles and dendrimers to inorganic gold or silica cores and biomimetic membrane-coated constructs. These platforms have demonstrated proof-of-principle for delivering chemotherapeutics, neuroprotective molecules and gene editors to models of brain tumours, Alzheimer’s disease and stroke. Ongoing challenges relate to immune clearance, long-term toxicity and scalable manufacture. Continued advances in materials science, combined with deeper insight into BBB biology, are accelerating the translation of nanoparticle technologies into viable therapies for central nervous system disorders.

Research from Nature Portfolio

A self-assembled supramolecular nanocarrier bearing optimised surface glycosylation was shown to exploit post-fasting glycaemic spikes for enhanced crossing of the BBB. By precisely tuning glucose density on the carrier, investigators achieved increased engagement of endothelial glucose transporter-1 and directed accumulation within neuronal tissue, demonstrating a controllable approach to regional drug deposition in the brain.

Focused ultrasound (FUS) has been used to transiently open endothelial tight junctions and facilitate nanoparticle delivery in preclinical models. A systematic study of gold nanoparticles of varying diameters revealed that medium-sized particles (around 15 nm) achieved the highest brain uptake in vivo, an outcome predicted by a computational model balancing permeation through ultrasound-induced gaps against vascular clearance rates.

Nanoparticle-Mediated Drug Delivery Across the Blood-Brain Barrier publication trend

The graph below shows the total number of articles in nanoparticle-mediated drug delivery across the blood-brain barrier across all publications each year (not limited to Nature Index journals).

Technical terms

Blood–brain barrier (BBB): A selective endothelial interface that regulates the passage of substances between the blood and the brain.

Nanoparticle: A nanoscale carrier, typically 1–100 nm in size, designed to transport therapeutic agents to specific biological targets.

Receptor-mediated transcytosis: A cellular uptake mechanism where ligands on nanoparticles bind to endothelial receptors to enable vesicular transport across the BBB.

Focused ultrasound (FUS): A noninvasive technique that uses acoustic energy to transiently open tight junctions of the BBB to enhance nanoparticle entry.

Glycosylation: The attachment of sugar moieties to nanoparticle surfaces to exploit glucose transport mechanisms at the BBB.

References

1. Blood-Brain Delivery Methods Using Nanotechnology. Pharmaceutics (2018).
2. Towards Improvements for Penetrating the Blood–Brain Barrier—Recent Progress from a Material and Pharmaceutical Perspective. Cells (2018).
3. Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain. Nature Communications (2017).
4. Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release. Advanced Science (2021).
5. Investigating the optimum size of nanoparticles for their delivery into the brain assisted by focused ultrasound-induced blood–brain barrier opening. Scientific Reports (2020).