Depression is a neuropsychiatric condition affecting 5% of the population and involving loss of interest, low mood, and anhedonia. Depression has been ranked as the third cause of the burden of disease worldwide in 2008 by the World Health Organization WHO. Depression molecular etiology is complex and still not fully understood. Common limitations of gold standard small molecule drugs include poor efficacy, off target side effects and difficult druggability of many targets. In this study we report a radically different approach deploying small engineered single domain antibodies (nanobody) targeting newly discovered glycine receptor mGlyR, an important player in mood regulation recently deorphanized. Using mouse model of stress induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solved an atomic structure of mGlyR bound to nanobody and used a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its effects on neural circuitry. These results pave the way for the new era of developing immunologics for intractable brain disorders.