Derived from the unique immune system of camelids, nanobodies are compact single-domainantibodies that have revolutionized the field of biomedical research. These miniaturized antibodies offer numerous advantages, including high specificity, stability, and ease of engineering. Interestingly, A2AR and mGlu5R form heteromers in the striatum, exhibiting synergistic transinhibition over striatal D2R signaling. 1 This oligomerization provides a unique pharmacological opportunity to explore whether the physical proximity of these receptors enables oligomer-dependent orthogonal targeting of counterpart receptors. In this context, we generated a mGlu5R specific nanobody (Nb43) bound to an active A2AR agonist (CGS21680) as a bivalent heteromer ligand with putative effects on dopaminergic signaling, which serves as a novel strategy for treating psychosis. In this study, validation of Nb43 binding specificity was determined in vitro and ex vivo. Furthermore, we observed that the presence of mGlu5R in transfected cells increases the potency of Nb43-CGS potency for A2AR. Additionally, we administered Nb43-CGS intracerebroventricularly to mice and observed a significant increase in catalepsy latency compared to control groups. This demonstrates the potential therapeutic efficacy of Nb43-CGS in vivo and further supports its development as a pharmacological intervention for conditions such as schizophrenia. These findings support the development of bivalent nanobody-based biodrugs as a promising and innovative pharmacological approach.1. Romero-Fernandez, W. et al. The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson’s Disease. Mol Neurobiol 59, 5955–5969 (2022).