Targeting mGlyR with nanobodies for depression

Nat Commun. 2026 Jan 26;17(1):831. doi: 10.1038/s41467-026-68339-x.

Abstract

Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Antidepressive Agents* / administration & dosage
  • Antidepressive Agents* / pharmacology
  • Depression* / drug therapy
  • Depression* / metabolism
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Glycine* / chemistry
  • Receptors, Glycine* / genetics
  • Receptors, Glycine* / immunology
  • Receptors, Glycine* / metabolism
  • Single-Domain Antibodies* / administration & dosage
  • Single-Domain Antibodies* / chemistry
  • Single-Domain Antibodies* / metabolism
  • Single-Domain Antibodies* / pharmacology
  • Single-Domain Antibodies* / therapeutic use

Substances

  • Single-Domain Antibodies
  • Receptors, Glycine
  • Antidepressive Agents