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

  • ACS Nano. 2026 Jun 2;20(21):15589-15605. doi: 10.1021/acsnano.6c04580.
Xiaolu Yu  1  2  3 ,  Xiao-Meng Deng  1  2  3 ,  Yi Lin  4 ,  Hongyu Ren  1  2  3 ,  Lu Jia  1  2  3 ,  Yanan Meng  1  2  3 ,  Fan Liu  1  2  3 ,  Qiang Cheng  4  5 ,  Zhao-Qian Teng  1  2  3 ,  Tuo Wei  1  2  3
Affiliations
  • 1. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 2. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4. Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
  • 5. Beijing Advanced Center of RNA Biology, Peking University, Beijing 100871, China.
PMID: 42157518 DOI: 10.1021/acsnano.6c04580
Abstract

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.

Keywords
brain disease therapy; brain-specific delivery; intranasal administration; lipid nanoparticle; mRNA delivery.
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