Tiny, antibody-like proteins found in camels, llamas, and alpacas could pave the way for a new generation of treatments for brain disorders such as schizophrenia and Alzheimer’s disease. Researchers from the Centre National de la Recherche Scientifique (CNRS) in Montpellier, France, report that these miniature molecules, known as nanobodies, can reach the brain more efficiently than traditional drugs and may offer therapy with fewer side effects. Their findings were published in Trends in Pharmacological Sciences, a journal of Cell Press.
Small but Powerful: What Makes Nanobodies Different
Nanobodies were first discovered in the early 1990s by Belgian scientists studying the immune systems of camels. Unlike conventional antibodies, which consist of two heavy and two light chains, camelids also produce antibodies made up of only heavy chains. The active part of these single-chain antibodies, or nanobodies, is about one-tenth the size of a regular antibody. This miniature size allows them to penetrate biological barriers, including the blood-brain barrier, a key obstacle in developing drugs for neurological diseases.
“Camelid nanobodies open a new era of biologic therapies for brain disorders and revolutionize our thinking about therapeutics,” said Philippe Rondard, co-corresponding author of the study. “We believe they can form a new class of drugs between conventional antibodies and small molecules.”
Breaking the Brain Barrier
Current antibody therapies have revolutionized treatments for cancers and autoimmune diseases, but their success in brain-related disorders remains limited. Large antibody molecules often cannot pass through the brain’s protective barriers, while smaller chemical drugs that can enter the brain tend to cause off-target effects due to their hydrophobic nature.
Nanobodies, in contrast, combine the specificity of antibodies with the mobility of small molecules. Their compact, water-soluble structure allows them to cross into brain tissue passively, without the need for complex transport systems. This property gives them an advantage in targeting proteins involved in neurological conditions.
“These are highly soluble small proteins that can enter the brain passively,” explained Pierre-André Lafon, co-corresponding author at CNRS. “Small-molecule drugs that cross the blood-brain barrier are often hydrophobic, which limits their bioavailability and increases the risk of side effects.”
From Mice to Medicine
In previous experiments, the CNRS team demonstrated that specific nanobodies could reverse behavioral deficits in mouse models of schizophrenia and other brain disorders. This proof-of-concept supports the idea that nanobodies can act on brain pathways that conventional drugs cannot easily reach.
Beyond their biological advantages, nanobodies are also easier to engineer, produce, and purify than traditional antibodies. Their simple structure makes it possible to fine-tune their properties to bind precisely to specific molecular targets, an important feature for designing customized therapies.
Next Steps Toward Human Trials
Despite the encouraging results in animal models, the researchers emphasize that several challenges remain before nanobody-based drugs can be tested in humans. Key steps include toxicology testing, long-term safety studies, and understanding the effects of chronic use. Scientists must also determine how long nanobodies persist in the brain and how often treatments would need to be administered.
“Regarding the nanobodies themselves, it is also necessary to evaluate their stability, confirm their proper folding, and ensure the absence of aggregation,” Rondard said. “We must also develop clinical-grade formulations that remain active during long-term storage and transport.”
The research team has already begun studying these parameters in brain-penetrant nanobodies. Lafon added that early results show the molecules remain stable and effective under conditions compatible with chronic treatment, an essential feature for long-term brain therapies.
Toward a New Class of Neurotherapeutics
Nanobodies’ unique combination of small size, high stability, and ease of modification could transform how scientists approach neurological drug design. If future studies confirm their safety and effectiveness in humans, these camelid-derived molecules might bridge the gap between traditional antibody therapies and small-molecule drugs, offering patients with brain disorders safer, more effective treatment options.