Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system

Systemic delivery of mRNA to the central nervous system (CNS) is severely restricted by the blood-brain barrier (BBB), which prevents most therapeutic molecules from reaching brain cells. While lipid nanoparticles (LNPs) have revolutionized mRNA delivery for vaccines and other peripheral applications, they typically accumulate in the liver rather than the brain. Overcoming this barrier is essential for treating neurological disorders and brain tumors.

The researchers designed and synthesized a library of 72 novel lipids by conjugating known BBB-crossing small molecules—such as L-DOPA, D-serine, and various neurotransmitter precursors—with amino lipids. They assembled these into lipid nanoparticles (BLNPs) and screened them for their ability to deliver mRNA to brain cells in vitro and in vivo. Through iterative structural optimization and formulation tuning, they identified a lead candidate, MK16, which was then evaluated for its biodistribution, cellular targeting, and therapeutic potential in disease models.

The lead formulation, MK16 BLNPs, demonstrated significantly higher mRNA delivery efficiency to the brain compared to conventional LNPs. Mechanistic studies revealed that MK16 BLNPs cross the BBB through a dual mechanism involving caveolae-mediated and gamma-secretase-mediated transcytosis. In vivo, these nanoparticles successfully delivered mRNA to neurons, astrocytes, and brain capillary endothelial cells. The platform showed therapeutic utility in two distinct models: it modulated drug-seeking behavior in a cocaine-conditioned place preference model by delivering DeltaFosb mRNA, and it significantly extended survival in an orthotopic glioblastoma model by delivering Pten mRNA. Importantly, the treatment was well-tolerated with no significant systemic toxicity observed.

This study provides a versatile, non-invasive platform for CNS-targeted gene therapy. By enabling the systemic delivery of mRNA to broad regions of the brain, this technology offers a promising new avenue for treating a wide range of neurological diseases, including addiction and aggressive brain cancers, without the need for invasive intracranial administration.