French researchers have developed a novel therapy using llama-derived nanobodies that cross the blood-brain barrier and significantly improve cognitive deficits in schizophrenia mouse models, after just a single injection.
Schizophrenia is a chronic and debilitating mental illness that affects approximately one percent of the global population and remains a leading cause of disability and premature death. While existing therapies have improved patient outcomes, they are relatively ineffective for negative and cognitive symptoms and are associated with a range of serious side effects. This is partially due to a lack of innovation, with most antipsychotics still only targeting dopamine receptors.
Breaking from the dopamine-centric paradigm, researchers at the Institute of Functional Genomics (CNRS/Inserm/Université de Montpellier) have focused on the glutamatergic system, specifically mGlu2 (metabotropic glutamate receptor 2). Growing evidence links the dysregulation of glutamate signaling to the cognitive and negative symptoms of schizophrenia. Published in Nature, the team engineered a bivalent nanobody that acts as a positive allosteric modulator, boosting the activity of mGlu2 receptors without triggering overstimulation.
Crucially, the nanobody was administered peripherally, through injection into a muscle or vein, and still reached the brain in sufficient concentrations to restore cognitive and sensorimotor function in preclinical schizophrenia models. The effect was rapid, and lasted up to seven days, despite only 0.1 percent of the nanobody crossing into the brain.
Compared to conventional treatments such as small molecules and antibodies, nanobodies are small, hydrophilic, and highly selective, with low immunogenicity and better tissue penetration. Their small size allows them to access targets in the brain that full-sized antibodies cannot reach, and their allosteric mechanism preserves natural patterns of receptor activity.
These results offer a proof of concept that nanobody-based agents could serve as a new class of long-acting, brain-penetrant drugs for psychiatric and neurological conditions. With further development, llama-derived nanobodies could open up an entirely new frontier in the treatment of schizophrenia and other neuropsychiatric diseases. While promising, it’s worth noting that previous therapies targeting the glutamatergic system have struggled to translate from animal models to human trials.
Nevertheless, with other recent approvals like Cobenfy, the first FDA-approved schizophrenia drug targeting cholinergic rather than dopamine receptors, the field is beginning to shift.
This nanobody approach could complement that progress, enabling new strategies to treat patients based on the specific neurochemical disruptions underlying their symptoms, and moving closer to personalized psychiatric care.
