Researchers at France's CNRS suggest camelid-derived nanobodies — tiny antibody fragments about ten times smaller than conventional IgG — might be engineered to cross the blood–brain barrier and target Alzheimer's hallmarks such as tau and amyloid‑β. Preclinical studies show promise, but major challenges remain, including ensuring stability, correct folding, avoidance of aggregation, understanding BBB transport and establishing safe dosing and storage. The team argues nanobodies could become a new drug class between antibodies and small molecules, yet clinical application will require more data and time.
Tiny 'Nanobodies' from Camels and Llamas Could Pave the Way for New Alzheimer's Therapies
Researchers at France's CNRS suggest camelid-derived nanobodies — tiny antibody fragments about ten times smaller than conventional IgG — might be engineered to cross the blood–brain barrier and target Alzheimer's hallmarks such as tau and amyloid‑β. Preclinical studies show promise, but major challenges remain, including ensuring stability, correct folding, avoidance of aggregation, understanding BBB transport and establishing safe dosing and storage. The team argues nanobodies could become a new drug class between antibodies and small molecules, yet clinical application will require more data and time.
21:05, 08.11.2025Science
Microscopic antibody fragments derived from camelids — animals such as camels, llamas and alpacas — are emerging as a promising platform for targeting brain diseases that have been difficult to treat, including Alzheimer's disease and schizophrenia.
What are nanobodies?
Conventional antibodies are large Y-shaped proteins the immune system uses to mark viruses, toxins and other unwanted material for removal. Nanobodies are streamlined, naturally occurring antibody fragments produced by camelids that are roughly ten times smaller than a typical Immunoglobulin G (IgG) antibody. Their small size allows them to penetrate tissue microenvironments that larger antibodies cannot.
Although similar small antibodies have been identified in sharks, camelid-derived nanobodies are particularly attractive for human therapeutics because they come from mammals and are more readily adapted to human biology.
Why they might work for brain diseases
For years, two major hurdles limited enthusiasm for brain-directed nanobody therapies: rapid clearance by the kidneys and the protective blood–brain barrier (BBB) that blocks many agents from entering the central nervous system. More recent preclinical studies, however, show that engineered nanobodies can be designed to cross the BBB, reach brain tissue and bind to pathological hallmarks of Alzheimer's disease — notably misfolded tau and amyloid-β proteins — helping to neutralize or promote clearance of these toxic species in animal models.
"Camelid nanobodies open a new era of biologic therapies for brain disorders and revolutionize our thinking about therapeutics," says Philippe Rondard, a neuropharmacologist at CNRS. "We believe they can form a new class of drugs between conventional antibodies and small molecules."
Key challenges before human use
Despite encouraging results, the CNRS review emphasizes several important preclinical and translational challenges. Researchers must:
- Verify nanobody stability, correct folding and absence of harmful aggregation.
- Clarify the precise mechanisms by which they cross the BBB and determine how long they persist in the brain to establish safe, effective dosing.
- Develop clinical-grade formulations that remain stable during long-term storage and transport and are compatible with chronic administration.
- Demonstrate favorable pharmacokinetics, manufacturability at scale, and long-term safety in humans.
Some engineering strategies — for example, modifications to extend half-life or fusion to carrier domains — are being explored to reduce rapid renal clearance, but each approach must be assessed for safety and efficacy in the brain context.
"These are highly soluble small proteins that can enter the brain passively," adds functional genomicist Pierre-André Lafon. "By contrast, small-molecule drugs designed to cross the blood–brain barrier are often hydrophobic, which can limit bioavailability, increase off-target binding and raise the risk of side effects."
At present, four nanobody-based therapies have regulatory approval, but none are approved for brain disorders. The CNRS team concludes that while camelid nanobodies could form a distinct therapeutic class between conventional antibodies and small molecules, translating them into safe, reliable medicines for neurodegenerative diseases will require additional data from rigorous preclinical and clinical studies.
Conclusion: The research, published in Trends in Pharmacological Sciences, highlights exciting potential but cautions that human treatments remain several years away. With careful optimization and testing, nanobodies could one day become a valuable tool in preserving memory and treating brain disease.