Bergamasco, M. I. | Search bioRxiv

bioRxiv2026

Non-invasive Bdnf mRNA therapy improves cognition in ageing and Alzheimers mouse models

Messenger RNA (mRNA) therapeutics have rapidly emerged as a transformative approach for treating a range of health challenges. Accelerated by the success of mRNA-lipid nanoparticle (LNP) vaccines during the COVID-19 pandemic, this platform holds promise beyond immunisation for the transient expression of therapeutic proteins in targeted tissues. Despite this promise, non-invasive delivery of mRNA to the brain, as with most therapeutics, remains a challenge due to the impermeability of the blood brain barrier. Here, we present a novel strategy to deliver neurotrophic factors to the brain via intranasal delivery of mRNA-LNP. As a proof of concept, we demonstrate that intranasal delivery of mRNA encoding the neurogenic factor BDNF (Brain Derived Neurotrophic Factor) enhances memory performance in both aged mice and a transgenic mouse model of Alzheimers disease. This approach offers a promising platform for delivering therapeutic proteins to the brain and opens new avenues for treating age-related and neurodegenerative disorders.

animal behavior and cognition↗

bioRxiv2026

Intranasal oxytocin mRNA-LNP can promote social behaviour and reduce pain

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 expression, 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/711938v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@131252aorg.highwire.dtl.DTLVardef@17efb79org.highwire.dtl.DTLVardef@1afe479org.highwire.dtl.DTLVardef@c0f2f5_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summaryIntranasal administration of mRNA-LNP enables local transfection in nasal epithelium and subsequent secretion of therapeutic oxytocin peptides into the brain, promoting social interactions and reducing pain.

neuroscience↗