Lipid Nanoparticle Platform Delivers mRNA to the Brain Through the Blood-Brain Barrier

Researchers at the Icahn School of Medicine at Mount Sinai say they have developed a lipid nanoparticle system capable of delivering messenger RNA (mRNA) to the brain via intravenous injection, a challenge that has long been limited by the protective nature of the blood-brain barrier.

The study (“Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system”) in mouse models and isolated human brain tissue was published in the online issue of Nature Materials. The researchers demonstrated the potential of this technology to pave the way for future treatments for a wide range of conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, brain cancer, and drug addiction, according to the scientists.

While previous research from Mount Sinai introduced a platform for transporting large biomolecules such as proteins and oligonucleotides into the central nervous system, this new study focuses on a different approach: using specially designed lipid nanoparticles to transport mRNA across the barrier.

Getting mRNA into the brain could allow scientists to instruct brain cells to produce therapeutic proteins that can help treat or prevent disease by replacing missing proteins, reducing harmful ones, or activating the body’s defenses.

“Our study shows that these blood–brain-barrier-crossing lipid nanoparticles (BLNPs) can safely and efficiently deliver mRNA into the brain,” said co-corresponding senior author Yizhou, Dong, PhD, PhD, professor of immunology and immunotherapy, and a member of the Icahn Genomics Institute and the Marc and Jennifer Lipschultz Precision Immunology Institute, at the Icahn School of Medicine at Mount Sinai. “This could open up opportunities to use mRNA-based therapies for a variety of neurological and psychiatric disorders.”

The research team designed and tested a library of lipids to optimize their ability to cross the blood-brain barrier. Through a series of structural and functional analyses, they identified a lead formulation, termed MK16 BLNP, that exhibited significantly higher mRNA delivery efficiency than existing lipid nanoparticles approved by the FDA. This system takes advantage of natural transport mechanisms within the blood-brain barrier, including caveolae- and γ-secretase-mediated transcytosis, to move nanoparticles across the barrier, the investigators said.

In studies using mouse models of disease, the BLNP platform successfully delivered therapeutic mRNAs to the brain, demonstrating its potential for clinical application.

“The systemic delivery of mRNA molecules to the central nervous system is challenging as they need to cross the blood-brain barrier (BBB) to reach into the brain. Here we design and synthesize 72 BBB-crossing lipids fabricated by conjugating BBB-crossing modules and amino lipids and use them to assemble BBB-crossing lipid nanoparticles for mRNA delivery,” the investigators wrote.

“Screening and structure optimization studies resulted in a lead formulation that has substantially higher mRNA delivery efficiency into the brain than those exhibited by FDA-approved lipid nanoparticles. Studies in distinct mouse models show that these BBB-crossing lipid nanoparticles can transfect neurons and astrocytes of the whole brain after intravenous injections, being well tolerated across several dosage regimens. Moreover, these nanoparticles can deliver mRNA to human brain ex vivo samples.

“Overall, these BBB-crossing lipid nanoparticles deliver mRNA to neurons and astrocytes in broad brain regions, thereby being a promising platform to treat a range of central nervous system diseases.”

“Our lipid nanoparticle system represents an important step in the effort to develop mRNA-based treatments for central nervous system disorders,” said Dong. “The study provides proof of concept that such an approach is viable and could be adapted for a range of diseases where gene therapy or mRNA therapeutics might play a role.”

The researchers noted that additional studies are needed to assess long-term safety and efficacy, including toxicology studies in accordance with FDA guidelines. Future research will focus on refining the technology for clinical translation.