Loo, L.; Fujikake, K.; Bergamasco, M. I.; Carr, R.; O'Shea, R.; Du, T.; Cohen, S. B.; Sandra, F.; Thordarson, P.; Martin, L.; Fong, C.; Neely, G. G.

The COVID-19 epidemic and success of mRNA-LNP vaccines demonstrated the transformative potential of mRNA therapeutics. Beyond vaccination, mRNA delivery offers a platform for transient on-demand expression of therapeutic proteins for both rare and common diseases. While delivery of therapeutics to the liver is relatively straightforward, targeted delivery of mRNA-LNPs to the central nervous system (CNS) remains a significant challenge. Here we show that intranasal mRNA-LNP delivery results in localized mRNA cargo uptake and functional expression in the respiratory and olfactory epithelium, where the encoded cargo protein is secreted and can enter the CNS. Guided by genomic data of pain-associated gene expression8, we identified secreted proteins as candidate mRNA-encoded analgesics. Intranasal mRNA-LNP encoding a synthetic oxytocin transcript (OXT) resulted in bioactive oxytocin peptide delivery to the CNS. Functionally, intranasal OXT mRNA-LNP enhanced social behaviour and attenuated pain responses across multiple behavioural paradigms, without impairing motor coordination. Importantly, repeated dosing was well tolerated and intranasal mRNA-LNP did not elicit an inflammatory response or alter overall health. Together, these findings establish intranasal mRNA-LNP delivery of secreted ligands as a safe, non-invasive route to target the CNS, unlocking a new class of mRNA therapeutics for pain or other disorders of the brain.