For decades, cognitive symptoms of schizophrenia have not been treated. Now, French researchers may have discovered a surprising ally: the camel’s immune system.
In a new study naturescientists at the Institute of Functional Genomics (CNRS/Inserm/Université de Montpellier) have developed a therapeutic nanodisease, an ultrasmall antibody fragment derived from Llamas – which can cross the blood-brain barrier and restore cognitive function in a mouse model of schizophrenia.
Targeting familiar receptors with new tools
The engineered nanodisease, known as DN13-DN1, is designed to target and enhance the activity of a specific brain receptor called metabolic glutamate receptor 2 (MGLU2), which plays a key role in regulating neural signaling. Although drugs targeting this receptor have been explored before, they often fail in late clinical trials due to poor specificity or unexpected side effects.
The reason for setting this nanomechanism is its accuracy. DN13-DN1 does not activate multiple receptor types, but binds only to MGLU2 homodimers, a configuration particularly relevant under the conditions of markings of glutamate system dysfunction (e.g., schizophrenia).
Very small size, very large result
Despite its small size (only 15 kg) DN13 – DN1 does something that most full-size antibodies can’t do: it crosses the blood-brain barrier. After a single intraperitoneal injection, it accumulates in key brain regions, including the cortex and ventral tolerant regions. The measured concentration was maintained for up to 7 days.
In two preclinical models, schizophrenia-like symptoms were simulated by NMDA receptor dysfunction, which is a hallmark of the disease:
- Mice treated with DN13-DN1 showed recovered recognition and working memory.
- Sensor movement gating is affected by many mental illnesses – and has also been corrected.
- Last for at least one week after a single dose.
Nano-organizations outperform traditional small molecule drugs and IgG-like antibody forms derived from the same molecule, which failed to produce behavioral improvements.
Beyond schizophrenia?
The study provides a compelling proof of concept that nanobody can be administered around and still has a therapeutic effect on the brain. Unlike many small molecules, the hydrophilicity and strict receptor selectivity of DN13-DN1 can reduce off-target effects and improve safety.
Interestingly, nanomechanisms have no effect on MGLU2 receptor expression or on fundamental behaviors such as movement or balance, indicating that their effects are both effective and specific.
Looking to the future
Although the mechanism by which DN13-DN1 enters the brain remains unclear, its successful penetration and sustained activity mark a promising step in psychiatric and neurological diseases based on nanodiseases. Humanization and security testing will be the next key step, but the path forward looks promising.
Posted in natureJuly 23, 2025
doi: 10.1038/s41586-025-09265-8
Title: Nanotherapy saves behavioral deficits in NMDA receptor dysfunction
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