Nanotechnology

Engineers refine lipid nanoparticles for better mRNA therapy

Chemical evolution of A3 lipids driven by A3 coupling reactions and activity and degradability. Credit: Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01267-7

Penn engineers have devised a new method to improve mRNA delivery and developed an optimal “recipe” for ionized lipids, the key ingredient in lipid nanoparticles (LNPs). This is the molecule behind COVID-19 vaccines and other innovative treatments. The method, described in Nature Biomedical Engineering, reflects an iterative process of developing dishes and could lead to safer and more effective mRNA vaccines and treatments.

Just as chefs experiment with taste and texture to perfect their dishes, the researchers used an iterative process to test variations and find the ideal structure for ionized lipids. The structure of this lipid influences the ability of LNPs to successfully deliver their contents, advancing mRNA therapies for vaccines and gene editing.

Breakthrough in LNP design

Nanoparticles have revolutionized the way mRNA vaccines and therapeutics are delivered by allowing them to move safely through the body, reach target cells, and release their contents efficiently. RNA is fragile on its own and dissolves without ever reaching its intended target.

At the heart of these nanoparticles are ionizable lipids, special molecules that can switch between charged and neutral states depending on the environment. This switch is essential for nanoparticle movement. In the bloodstream, ionized lipids remain neutral and prevent toxicity. However, upon entering the target cell, they become positively charged, triggering the release of the mRNA payload.

Researchers led by Michael J. Mitchell, associate professor of bioengineering, improved this delivery process by optimizing the structure of the ionized lipid. Going beyond existing methods limited by speed-accuracy trade-offs, the team developed a step-by-step “directed chemical evolution” process.

Through five cycles, each further purified the lipids and created dozens of high-performance biodegradable lipids. Some of them exceeded industry standards.

The secret sauce: direct chemical evolution

To develop safer and more effective ionized lipids, Penn engineers took a unique approach that combines two common methods. One is medicinal chemistry, in which molecules are slowly and painstakingly designed one step at a time, and the other is combinatorial chemistry, in which many different molecules are rapidly produced. A simple reaction. The former has high accuracy but low speed, and the latter has low accuracy but high speed.

“We thought we might have the best of both worlds,” says Xuexian Han, lead author of the paper and most recently a postdoctoral fellow at the Mitchell Institute. “It’s fast and accurate, but we had to think outside the traditional box of the field.”

By borrowing the idea of ​​directed evolution, a technique used in both chemistry and biology that mimics the process of natural selection, the researchers combined precision and rapid output to create ideal lipids. Achieved the recipe.

The process begins with the generation of a wide variety of molecules that are screened for their ability to deliver mRNA. The best-performing lipids are then used as a starting point to generate another round of molecular variants, which is repeated until only the best-performing variants remain.

Breakthrough: Penn engineers refine lipid nanoparticles for better mRNA therapy

Members of the Mitchell Institute, including Mr. Xueshan Han on the left and Mr. Michael Mitchell in the center. Credit: Xuexiang Han, Mike Mitchell

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Innovative material: A3 coupling

A key contribution to the team’s recipe for improving ionized lipids is the A3 coupling, a three-component reaction named after the chemical components amine, aldehyde, and alkyne.

This reaction has never been utilized to synthesize ionized lipids for LNPs, uses inexpensive commercially available raw materials, and produces only water as a byproduct, allowing for rapid production of the large number of ionized lipid variants needed. It is a cost-effective and environmentally friendly option for As a material for directional evolution.

“We found that the A3 reaction is not only efficient, but also flexible enough to precisely control the molecular structure of the lipids,” says Mitchell. This flexibility was key to fine-tuning the properties of ionized lipids for safe and effective mRNA delivery.

Why this progress matters

This new method for designing ionizable lipids is expected to have broad implications for mRNA-based vaccines and therapeutics poised to treat conditions ranging from genetic disorders to infectious diseases. I am.

In this study, optimized lipids improved mRNA delivery in preclinical models for two high-priority applications. One is editing the gene that causes hereditary amyloidosis, a rare disease that causes abnormal protein deposits throughout the body, and the other is improving the delivery of COVID-19 mRNA vaccines. . In both cases, the engineered lipids performed better than current industry standard lipids.

Beyond these specific applications, new approaches have the potential to accelerate the development of mRNA therapeutics overall. Developing effective lipids using traditional methods can take years, but the team’s directed evolutionary process can shorten this timeline to just months or even weeks. Possibly.

“Our hope is that this approach will accelerate the pipeline of mRNA therapeutics and vaccines, bringing new treatments to patients faster than ever before,” Mitchell said.

New frontiers in mRNA delivery

LNPs are a safe and flexible method for delivering genetic material, but their success depends on the properties of ionizable lipids. Penn Engineers’ iterative design process allows researchers to refine these lipids with unprecedented speed and precision, bringing next-generation mRNA therapeutics closer to reality.

With this innovative recipe for LNP, Penn engineers have taken a major step forward in the advancement of mRNA technology, offering hope for a faster and more efficient path to life-changing treatments.

Further information: Xuexiang Han et al, Optimization of the activity and biodegradability of ionizable lipids for mRNA delivery via Directed Chemical Evolution, Nature Biomedical Engineering (2024). DOI: 10.1038/s41551-024-01267-7

Provided by University of Pennsylvania

Citation: Engineers refine lipid nanoparticles for better mRNA therapies (November 22, 2024) https://phys.org/news/2024-11-refine-lipid-nanoparticles-mrna-therapies. Retrieved November 24, 2024 from html

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