For decades, the cognitive symptoms of schizophrenia have defied treatment. Now, researchers in France may have found a surprising ally: the immune system of llamas.
In a new study published in Nature, scientists at the Institute of Functional Genomics (CNRS/Inserm/Université de Montpellier) have developed a therapeutic nanobody—an ultra-small antibody fragment derived from llamas—that can cross the blood-brain barrier and restore cognitive function in mouse models of schizophrenia.
Targeting a Familiar Receptor With a Fresh Tool
The engineered nanobody, dubbed DN13–DN1, is designed to target and enhance the activity of a specific brain receptor called metabotropic glutamate receptor 2 (mGlu2), which plays a key role in regulating neural signaling. Although drugs targeting this receptor have previously been explored, they have often failed in late-stage clinical trials due to poor specificity or unintended side effects.
What sets this nanobody apart is its precision. Rather than activating multiple receptor types, DN13–DN1 binds exclusively to the mGlu2 homodimer, a configuration especially relevant in conditions marked by glutamate system dysfunction, such as schizophrenia.
Small Size, Big Results
Despite its tiny size—just 15 kilodaltons—DN13–DN1 does what most full-size antibodies cannot: it crosses the blood-brain barrier. After a single intraperitoneal injection, it accumulated in critical brain regions including the cortex and ventral tegmental area. Measured concentrations remained effective for up to seven days.
In two preclinical models simulating schizophrenia-like symptoms through NMDA receptor hypofunction, a hallmark of the disease:
- Mice treated with DN13–DN1 showed restored recognition and working memory.
- Sensorimotor gating—impaired in many psychiatric disorders—was also corrected.
- These effects persisted for at least a week after a single dose.
The nanobody outperformed both traditional small-molecule drugs and an IgG-like antibody format derived from the same molecule, which failed to produce behavioral improvements.
Beyond Schizophrenia?
The study offers compelling proof of concept that nanobodies can be administered peripherally and still exert therapeutic effects on the brain. Unlike many small molecules, DN13–DN1’s hydrophilic nature and strict receptor selectivity may reduce off-target effects and improve safety.
Interestingly, the nanobody showed no impact on mGlu2 receptor expression or on basic behaviors like locomotion or balance, suggesting that its action is both effective and specific.
Looking Ahead
While the mechanism by which DN13–DN1 enters the brain remains partly unclear, its successful penetration and sustained activity mark a promising step toward nanobody-based therapies for psychiatric and neurological disorders. Humanization and safety testing will be key next steps, but the road forward looks promising.
Published in Nature, 23 July 2025
DOI: 10.1038/s41586-025-09265-8
Title: Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction
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