Peptide-Mediated Drug Delivery Across The Blood-Brain Barrier

The blood–brain barrier (BBB) is a selectively permeable interface formed by specialised endothelial cells, tight junctions and supporting pericytes and astrocytic endfeet. Its principal role is to maintain cerebral homeostasis by restricting entry of most therapeutics, especially macromolecules and hydrophilic agents. Peptide-mediated strategies exploit short amino-acid sequences to ferry drugs across this barrier via mechanisms such as receptor-mediated transcytosis, adsorptive-mediated uptake and direct membrane translocation. Shuttle peptides are designed to bind specific BBB receptors (for example transferrin or low-density lipoprotein receptor-related protein 1) and trigger endocytosis, while cell-penetrating peptides (CPPs) use electrostatic interactions to traverse endothelial membranes. Conjugation of these peptides to small molecules, proteins, nucleic acids or nanocarriers has enabled targeted delivery, enhanced brain accumulation and reduced peripheral toxicity. Advances include hierarchical assembly of phage-derived peptides into nanoligand carriers, optimisation of multivalent ligand avidity to favour tubular transcytosis and discovery of novel sequences through in vitro phage display. These developments offer promise for the treatment of neurological disorders such as Alzheimer’s disease, glioma and viral encephalitis by improving central nervous system bioavailability of otherwise impermeant therapeutics.

Research from Nature Portfolio

Recent studies have shown that hierarchical assembly of a brain-specific phage display peptide into NanoLigand Carriers enables precise targeting of cerebral endothelial receptors, notably the transferrin receptor and RAGE, triggering receptor-mediated transcytosis and delivery of siRNA cargo into neurons and glia. Intravenous administration of these constructs complexed with BACE1 siRNA achieved efficient enzyme down-regulation in the brain without observable inflammation, demonstrating both safety and functional gene silencing. This approach expands the repertoire of active targeting by combining multivalent peptide architecture with established RNA interference modalities, overcoming prior limitations in specificity and efficacy of nanoparticle-based brain delivery.

Peptide-Mediated Drug Delivery Across The Blood-Brain Barrier publication trend

The graph below shows the total number of articles in peptide-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 physical and biochemical barrier formed by brain endothelial cells, tight junctions, pericytes and astrocyte endfeet that regulates passage of substances from blood to brain.

Receptor-mediated transcytosis: The process by which ligands bound to specific endothelial receptors are internalised in vesicles and transported across cells to the opposite membrane.

Phage display: A screening technique in which libraries of peptide-expressing bacteriophages are used to identify sequences with high affinity for target receptors or surfaces.

Cell-penetrating peptides (CPPs): Short, often cationic peptides capable of crossing cellular membranes and delivering cargoes by direct translocation or endocytosis.

Peptide-drug conjugate (PDC): A bioactive therapeutic in which a peptide shuttle is covalently linked to a drug or imaging agent to facilitate targeted delivery across biological barriers.

References

1. Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide. Nature Communications (2019).
2. On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias. Science Advances (2020).
3. Novel Blood–Brain Barrier Shuttle Peptides Discovered through the Phage Display Method. Molecules (2020).
4. Penetrating the Blood-Brain Barrier with New Peptide–Porphyrin Conjugates Having anti-HIV Activity. Bioconjugate Chemistry (2021).