Revolutionary lipid nanoparticle-mRNA delivery system transforms neurological treatment and beyond

Messenger ribonucleic acid (mRNA)-based therapeutics and the potential of mRNA as a treatment for various conditions has been researched for decades. A key challenge remains finding a delivery system that enables enough of the mRNA to reach target tissues safely without causing adverse effects. Lipid nanoparticles have been studied since the 1960s, but widespread use and optimization of delivery for mRNA therapeutics, including vaccines, really came to the forefront during COVID-19. While these vaccines saved countless lives, current lipid nanoparticle-mRNA delivery systems still face limitations that researchers are working to improve for broader therapeutic use.

Scientists with The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and The University of California at Berkeley have worked together since 2016 to craft more advanced delivery methods for gene-editing tools. A portion of this work is developing lipid nanoparticle-mRNA complexes that are more effective and safer than ever before, even in difficult-to-treat regions like the brain.

"We [UT Health San Antonio researchers] are the brain scientists, and they [UC Berkeley researchers] are the bioengineering group. We made a perfect team to pursue our goal to deliver therapeutics to the brain safely and efficiently," said one of the UT Health San Antonio members of this collaboration, Hye Young Lee, PhD, associate professor in the Department of Cellular and Integrative Physiology, Joe R. and Teresa Lozano Long School of Medicine.

Delivery of mRNA package a challenge

MRNA is a type of genetic material that carries instructions (messages) to cells for making certain proteins. It is fragile and essentially useless if it degrades before it reaches its destination. Lipid nanoparticles are extremely small, fatty substances that are used to encase the mRNA package to protect it from being broken down in the body before it reaches its destination. Once the lipid nanoparticle-mRNA complex enters the body, the lipid nanoparticles fuse to other lipids in the cell wall, allowing the mRNA to enter. After the lipid nanoparticle is unlocked, the mRNA is released and enters the cell to begin processing proteins. That protein then triggers the desired immune response (in the case of vaccines) or therapeutic effect.

Limited information of mRNA delivery in the brain

Lee was the primary investigator of a study published in Biochemistry in 2023, together with the UC Berkeley lab, that showed, for the first time, a lipid nanoparticle-mRNA system deliver mRNA material of the gene editing tool, CRISPR (clustered regularly interspaced short palindromic repeats) to portions of the brain. Previous limits of lipid nanoparticle-mRNA therapeutics for neurological conditions have been the inability to deliver larger proteins into the brain, low tissue penetration and minimal transfection efficiency (how effectively mRNA material is delivered and expressed in target cells). This study provides information for potential mRNA treatments of complex neurological disorders, including Alzheimer's disease, epilepsy, glioblastoma, seizures and Fragile X syndrome, a genetic condition linked to autism spectrum disorder.

Calculated corrosion

Currently, standard lipid nanoparticle-mRNA complexes can only deliver between 1% and 4% of their mRNA payloads into the cytoplasm. Additionally, lipid nanoparticles contain lipids that can trigger inflammation and damage body cells. They are also highly toxic and can linger in tissues. For these reasons, these therapeutics have not been able to be used for extended periods of time, and dosages are limited.

The latest success from these UT Health San Antonio and UC Berkeley scientists is a study published in August 2024 in Nature Nanotechnology that suggests a lipid nanoparticle-mRNA structure created to rapidly deteriorate at the correct time greatly improves the delivery of mRNA into tissues like the liver, spleen, lungs and brain. The teams found that the addition of an acid-degradable azido-acetal compound results in highly stable lipid nanoparticles that break down quickly, allowing for better treatment delivery. The study found that this new system transfected 90% of cells in the liver; 25% in the spleen; 30% in the brain; and about 50% in lung cells. This breakthrough could exponentially expand the possibilities of mRNA-based treatments.

Cross-country collaboration

Lee said the pairing of the two universities over the past eight and a half years has led to five published studies (with another two on the way) and multiple grants, including funding from the National Institutes of Health.

The teams communicate frequently and send lab materials back and forth as needed. However, sending the extremely temperature-sensitive lipid nanoparticles, which must be kept at freezing temperatures, between sunny California and even hotter Texas proved to be quite the challenge. After a couple ruined samples, they learned the best method for ultra-fast, icy cool delivery.

Even with its challenges, Lee said there is massive potential for mRNA-based therapeutics for neurological and other conditions. While the creation of gene-editing therapeutics has quickly advanced, delivery systems for these tools have failed to keep pace.

"Scientists started to produce gene editing therapeutics in the clinical setting, so we urgently need to figure out the delivery system for these gene-editing tools," Lee said.

Her lab, along with the UC Berkeley team, will continue to strive for even more advanced versions of lipid nanoparticle-mRNA complexes and other gene-editing tools that overcome the limitations of existing systems.

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