Nose-to-Brain Delivery of mRNA-Loaded Lipid Nanoparticles Bypasses the Blood-Brain Barrier for Effective Brain Disease Therapy.

mRNA-loaded lipid nanoparticles (mRNA-LNPs) show great therapeutic potential, but their use in central nervous system (CNS) disorders is limited by poor blood-brain barrier (BBB) penetration. Intranasal (IN) administration can bypass the BBB via olfactory/trigeminal pathways, enabling direct brain targeting and rapid screening of brain-specific lipid nanoparticles (LNPs). Using a peptide-based ionizable lipid platform, we systematically evaluated how LNP surface charge affects IN brain delivery and found that positively charged mRNA-LNPs produced superior brain transfection. Iterative in vivo screening yielded an intranasal brain-targeting LNP (INBT LNP) that efficiently traverses the olfactory and trigeminal nerves, drives brain-specific mRNA expression, and minimizes off-target expression in peripheral organs. Co-delivery of mRNAs encoding brain-derived neurotrophic factor (BDNF) and interleukin-10 (IL-10) using INBT LNPs significantly reduced neuroinflammation, inhibited neuronal death, and improved cognition in a repetitive mild traumatic brain injury (rmTBI) mouse model. Overall, this work establishes a noninvasive, patient-compliant, intranasal mRNA-LNP platform for brain delivery, offering a promising therapeutic strategy for TBI and other CNS disorders.