The blood–brain barrier (BBB) remains one of the greatest challenges in developing effective biologics for neurological diseases. Neurodegenerative conditions — Alzheimer’s, Parkinson’s, ALS and frontotemporal dementia — collectively represent an urgent global health challenge, yet most therapeutic candidates fail because they simply cannot reach their targets within the CNS.

In their latest industry insight, Biointron highlights the rapid evolution of BBB-penetrant antibody and biologic delivery strategies, and how these innovations are reshaping CNS drug development.

The BBB: a selective gateway blocking most biologics

Biointron emphasises that the BBB remains an exceptionally stringent biological checkpoint:

• Over 98% of small molecules fail to cross it.

• Monoclonal antibodies (~150 kDa) penetrate at only ~0.1% of systemic levels.

• Neurodegenerative pathology distorts endothelial transport, further reducing drug access.

The BBB’s architecture — tight junction-rich endothelial cells, pericytes and astrocytic end-feet, ensures metabolic stability but creates immense challenges for therapeutic delivery.

Receptor-Mediated Transcytosis (RMT): the leading approach highlighted by Biointron

Biointron’s overview reinforces that RMT has become the most promising mechanism for delivering antibodies, enzymes and engineered biologics into the brain.
Key insights include:

• Moderate-affinity, monovalent binding to transferrin receptor (TfR1) enables efficient transcytosis without receptor degradation.

• Bispecific antibodies, such as therapeutic-TfR1 shuttles (e.g., Trontinemab), are showing improved CNS exposure and amyloid-target engagement.

• BBB shuttles are expanding beyond antibodies, now applied to enzymes, ASOs, nanoparticles and even viral vectors.

• Target choice matters: TfR1 offers fast uptake but faster degradation, while CD98hc can promote slower but more sustained brain exposure.

Complementary approaches: adapting delivery for the next generation of CNS biologics

Biointron notes several other approaches gaining traction:

1. Focused Ultrasound (FUS) with microbubbles

A non-invasive method that temporarily and regionally opens the BBB — showing synergy with antibody therapies in Alzheimer’s models.

2. Engineered nanoparticles, exosomes and ligand-functionalised carriers

These systems leverage BBB-targeting motifs such as transferrin or LRP1, although scalability and regulatory-grade reproducibility remain barriers.

3. Intranasal and compartmentalised delivery

These bypass the BBB entirely and offer direct access to CNS regions with fewer systemic side effects.

Technologies enabling BBB-focused biologic engineering

Biointron highlights several tools accelerating innovation:

• 89Zr-immunoPET imaging for tracking biologic movement across the BBB in vivo.

• BBB-on-chip systems, brain organoids and microfluidics for more predictive translational modelling.

• High-throughput screening and machine-learning platforms to optimise affinity, valency, endosomal trafficking and CNS exposure.

Together, these techniques are allowing researchers to transition from empirical trial-and-error to rational, data-driven BBB engineering.

The Future: Designing with the BBB, not against it

What emerges clearly in Biointron’s commentary is a major shift in mindset:
The BBB is no longer an obstacle. It is now a design partner.

As biologic engineering, structural modelling, receptor biology and quantitative imaging converge, next-generation antibodies and biologics can be custom-built to engage BBB transport pathways intentionally — enabling precise CNS targeting previously considered impossible.

Biointron’s perspective is clear: companies that integrate antibody engineering, bispecific design, affinity optimisation and manufacturability assessment stand to lead the next wave of CNS drug innovation.

Summary 

Biointron’s analysis underscores a pivotal moment in CNS drug development: BBB transport is becoming programmable. Advances in transcytosis-based shuttles, focused ultrasound, engineered nanoparticles and high-resolution imaging are enabling truly brain-penetrant biologics.

For teams exploring CNS mechanisms, validating new targets, or developing BBB-penetrant antibodies and modalities, these insights are critical.

Find out more from Biointron here!