Single Nanobody Injection Reverses Schizophrenia Symptoms
A single nanobody injection reversed memory and thinking problems in mouse models of schizophrenia.
What if a single injection could improve memory and thinking problems linked to schizophrenia?
Researchers at the Institute of Functional Genomics in Montpellier, France, have taken a step in that direction. In a study published in Nature, they describe a nanobody, made from llama antibodies, which crosses into the brain and reverses cognitive and sensorimotor deficits in mouse models of the disease.
Current schizophrenia treatments fail to address cognitive symptoms
Schizophrenia affects ~1% of people worldwide. Current medications mostly target positive symptoms like hallucinations and delusions; however, they do little for the memory, attention and reasoning problems that make everyday life harder for many patients. These cognitive symptoms are strongly linked to poorer long-term outcomes, yet there are no widely effective treatments for them.
One theory in schizophrenia research focuses on glutamate signalling in the brain – specifically, reduced function of N-methyl-d-aspartate (NMDA) receptors. Drugs that indirectly target this pathway, such as mGlu2/3 receptor agonists or positive allosteric modulators, although initially promising, mostly failed in late-stage clinical trials. One likely reason is that the compounds weren’t selective enough and may have been less effective in patients already treated with antipsychotics, which can reduce mGlu2 expression.
“There is an urgent need for efficient and innovative therapies to treat brain disorders such as psychiatric and neurodegenerative diseases,” the authors said.
Antibody-based drugs could be an option, offering high specificity with fewer off-target effects. However, full-size antibodies are too big to reliably cross the blood–brain barrier, making them difficult to use for brain diseases.
Nanobodies are small, single-domain antibodies, originally found in camelids, that are approximately a 10th of the size of conventional antibodies. They’re easier to produce, highly specific and some have been shown to reach the brain.
The team set out to design a nanobody that could cross into the brain after a standard injection, boost activity at the mGlu2 receptor and improve cognition in mouse models of schizophrenia.
New nanobody therapy improves memory and behaviour in schizophrenia models
The new nanobody, called DN13–DN1, was made by combining two fragments: one that boosts mGlu2 receptor activity and another that binds without activating it. Linking these together increased the molecule’s potency and time spent at its target.
The team injected the nanobody into the abdomen of mice and tracked its movement using multiple methods. Despite its small size, DN13–DN1 crossed the blood–brain barrier and reached key brain areas such as the cortex and hippocampus – regions rich in mGlu2 receptors. The nanobody stayed in the brain for at least seven days after just one injection.
To test whether this nanobody could improve symptoms linked to schizophrenia, they used two mouse models with reduced NMDA receptor function – one caused by early-life exposure to phencyclidine, the other a genetic model (GluN1-KD) that mimics a rare human disorder. Both models show cognitive and sensory deficits similar to those seen in people with schizophrenia.
DN13–DN1 improved memory in tasks such as novel object recognition and the Y-maze. It also improved sensorimotor gating, a process often impaired in schizophrenia. These effects lasted at least a week – far longer than the standard mGlu2/3 drug LY379268, which wore off within 24 hours.
Sensorimotor gating
A brain process that filters out irrelevant sensory information, allowing someone to focus attention and respond appropriately. It's often impaired in people with schizophrenia.
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DN13–DN1 also had no effect in healthy mice, nor did it change overall activity levels or alter mGlu2 expression.
A larger antibody version (DN13–Fc) failed to improve behaviour or reach the brain, highlighting the importance of the nanobody’s small size.
Repeated low-dose injections over several weeks also produced sustained improvements with no signs of toxicity.
The future of schizophrenia treatment development
This study shows it’s possible to deliver nanobodies into the brain using a simple injection. DN13–DN1 is more targeted and longer-acting than standard small molecules, and it only boosts mGlu2 activity when the natural ligand is present, which may reduce side effects such as overstimulation.
DN13–DN1 also avoids the off-target effects seen with many hydrophobic drugs, making it a strong candidate for further development, and not just for schizophrenia, but for other brain conditions involving glutamate signalling.
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The findings could help bring mGlu2 back into focus as a drug target. DN13–DN1 sidesteps the problems seen in previously failed trials of mGlu2 drugs, by acting only on mGlu2 homodimers and working even when receptor expression is low, as in GRIN disorders.
GRIN disorders
Rare genetic conditions caused by mutations in genes that affect NMDA receptors, leading to symptoms that overlap with schizophrenia, such as cognitive impairment and seizures.
More work is needed before clinical use; the nanobody will need to be “humanised” to avoid immune reactions, and its long-term safety must be tested. Researchers will also need to find the best dosing strategies and delivery routes – intravenous, subcutaneous or intranasal – and test it in other diseases.
“Our study opens new routes for the clinical management of brain diseases with nanobody-based immunotherapies using low-frequency, peripheral administration,” said the authors.
Reference: Oosterlaken M, Rogliardo A, Lipina T, et al. Nanobody therapy rescues behavioural deficits of NMDA receptor hypofunction. Nature. 2025. doi: 10.1038/s41586-025-09265-8
This article is a rework of a press release issued by the French National Centre for Scientific Research. Material has been edited for length and content.
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