Applications · Neurology

Crossing the blood–brain barrier on purpose

The blood–brain barrier is a tightly sealed endothelial wall with efflux pumps and no fenestrations, built to keep molecules out of the central nervous system. Getting nucleic acids across it intact is the single hardest delivery problem in the field.

4.8×: CNS exposure
21 days: Knockdown duration
< 1%: Unaided dose reaching brain

Overview

Why delivery decides outcomes in neurology

Around 98% of small molecules and effectively all large biologics fail to cross the blood–brain barrier. Oligonucleotides are large, polyanionic and rapidly cleared, so direct injection into cerebrospinal fluid or brain tissue has been the practical route for most approved CNS nucleic-acid drugs.

Receptor-mediated transcytosis offers a way through. Carriers decorated with ligands for the transferrin receptor, the insulin receptor or the LDL-receptor-related protein 1 are recognised by brain endothelial cells and ferried across without opening the barrier. Antibody shuttles against these receptors have shown a measurable increase in brain exposure for enzymes and oligonucleotides.

Once across, the carrier still has to release its cargo inside the right cells. Neurons are post-mitotic and hard to transfect; microglia and astrocytes take up particles more readily. Cell-type selectivity in the brain, rather than crossing alone, is the next frontier.

Delivery barriers

What stands in the way

Tight junctions and efflux

Claudin and occludin junctions block paracellular passage, while P-glycoprotein and BCRP pump many small molecules back into the blood.

Off-target trapping

Liver and spleen capture most intravenously dosed particles before they reach brain capillaries; only a small fraction of the dose is ever presented to the barrier.

Slow transcytosis

Receptor-mediated transport across the endothelium is saturable. The density and avidity of the targeting ligand must be tuned so the particle is carried across rather than retained in the endothelial cell.

Long-lived effect

Neurons do not divide, so a single knockdown can persist for weeks. That cuts dosing frequency but makes any off-target silencing proportionally harder to undo.

Routes of administration

Systemic and direct routes are complementary rather than competing. Intravenous carriers are the least invasive and can reach wide brain regions, but they face the full clearance machinery. Intrathecal and intracerebroventricular dosing bypasses the barrier entirely and needs far lower doses, at the cost of a procedure.

Intravenous with receptor-targeted carriers: non-invasive, distributed delivery, dose limited by peripheral clearance.
Intrathecal lumbar injection: widespread spinal and cortical exposure, routine in antisense and siRNA programmes.
Intracerebroventricular delivery: very high local concentration, suitable for enzyme replacement and focal targets.
Focused ultrasound with microbubbles: transiently opens the barrier at a chosen site and lets conventional carriers through.

Payloads designed for the CNS

Antisense oligonucleotides and siRNA are the most advanced CNS nucleic-acid drugs. Chemically modified antisense oligonucleotides are stable in cerebrospinal fluid and have produced durable knockdown of huntingtin and SOD1 in trials, showing that the biology is tractable when delivery is solved.

mRNA and CRISPR payloads are earlier. Expression from mRNA lasts days, which suits enzyme replacement for metabolic brain disorders, while CRISPR editing in post-mitotic neurons aims at permanent correction of monogenic forms of disease.

Measuring brain exposure

Brain delivery claims are easy to overstate. Whole-brain homogenate fluorescence counts particles still in capillaries and endothelial cells, not particles that reached neurons. Careful programmes combine intravascular staining to subtract the vascular fraction, imaging of live animals over time, and cell-type-resolved readouts.

Functional endpoints matter more than concentration. A carrier that delivers four-fold more oligonucleotide but silences the target twice as well in the intended cell type is the better carrier.

Payloads

What gets delivered, and what it needs

Payload	CNS use case	Delivery requirement
Antisense oligonucleotide	Knockdown of disease genes such as SOD1, HTT, C9orf72	Stable in CSF; neuronal uptake after intrathecal dosing
siRNA	Sustained silencing in glia and neurons	Cytoplasmic release; RISC loading
mRNA	Transient enzyme or growth-factor replacement	Cytoplasmic release; low innate activation in CNS
Plasmid DNA	Long-term expression of neurotrophic factors	Nuclear entry in slowly dividing tissue
CRISPR RNP	Permanent correction of monogenic neurological disease	Fast release before protein degradation

How success is measured

Brain-to-blood exposure ratio with a vascular marker to subtract circulating carrier
Target knockdown by qPCR and protein measurement in cortex, hippocampus and spinal cord
Cell-type distribution by confocal imaging of neurons, astrocytes and microglia
Behavioural and electrophysiological endpoints in disease models
Neuroinflammation and glial activation as safety markers

Browse the Assay Library →

Programmes in this area

BB-318
CNS oligonucleotide shuttle — neurodegeneration
Preclinical · ETH Molecular Systems

See the full pipeline →

Other application areas

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