Unveiling the Power of mRNA and LNPs in Modern Medicine

Messenger RNA (mRNA) delivers genetic instructions to produce specific proteins within cells, which can neutralize harmful cellular elements or trigger desired immune responses.

Lipid nanoparticles (LNPs) serve as the delivery agents that transport these delicate mRNA molecules to their target cells via the bloodstream, efficiently and safely bypassing the body's defenses to ensure effective delivery.

However, the synthesis of cationic lipids, a positively charged lipid type that is an essential component of LNPs, is frequently a time-consuming process that involves multiple steps of chemical synthesis and purification, much like building an advanced stealth vehicle.

To overcome this difficulty, Michael Mitchell and colleagues at the University of Pennsylvania have developed a unique method that uses a compound library fabrication process called "click-like chemistry" to produce LNPs in a single, easy step.

Their research, which was published in the journal Nature Chemistry, demonstrates that this technique not only expedites the synthesis process but also offers a means of fitting these delivery vehicles with a "GPS" to more precisely target particular organs like the spleen, liver, and lungs.

This could lead to the discovery of new treatment options for a variety of illnesses that affect these organs.

We’ve developed what we call an amidine-incorporated degradable (AID) lipid, a uniquely structured biodegradable molecule. Think of it as an easy-to-build custom mRNA vehicle with a body kit that informs its navigation system. By adjusting its shape and degradability, we can enhance mRNA delivery into cells in a safe manner. By adjusting the amount of the AID lipid that we incorporate into the LNP, we can also guide it to different organs in the body, much like programming different destinations into a GPS.”

Michael Mitchell, Associate Professor and Director, Department of Bioengineering in the School of Engineering and Applied Science, University of Pennsylvania

First author Xuexiang Han, a former postdoctoral researcher in the Mitchell Lab, explains that, as opposed to the weeks-long process typically needed, their new approach allows the rapid creation of diverse lipid structures in just one hour.

The result is a significant acceleration in the development and testing of AID-lipids. This will enable us to explore a broader range of lipid compositions and their effects on mRNA delivery.”

Xuexiang Han, Study First Author, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences

The researchers synthesized the AID-lipids using a tandem multicomponent reaction (T-MCR), which combines three chemical compounds—an amine, a thiol, and an acrylate—in a single step to quickly produce a variety of lipid structures, to achieve these accelerated AID-lipid builds.

The one-pot synthesis method is a more effective and scalable method for delivering mRNA-LNP because it drastically cuts down on the amount of time required to create cationic lipids.

Mitchell's group created 100 distinct AID-lipids, which were subsequently combined to create LNPs. When the produced LNPs were tested in animal models for their capacity to deliver mRNA to different organs, the researchers saw that they could precisely target particular organs.

The incorporation of degradable components into AID-lipids is a crucial characteristic that guarantees the safe breakdown of LNPs within the body following the delivery of their mRNA payload. To reduce the possibility of adverse effects and make sure that the medicinal agents do not build up in the body over time, biodegradability is crucial.

The ability of the AID-lipid LNPs to efficiently transfer mRNA encoding functional proteins was demonstrated by the researchers, underscoring the potential of these compounds for a variety of therapeutic uses.

The discovery of a unique head (or tail) ring-alkyl aniline structure, which was especially successful in improving mRNA delivery, was another important discovery. This structure, which the researchers named the "wedge effect," makes it easier for the LNPs to pass through cellular membranes and allows mRNA to be released into the target cells.

According to the study, LNPs with this structure outperformed LNPs without it in terms of transfection efficiency and protein expression levels.

The ability of AID-lipid LNPs to deliver mRNA vaccines that target particular immune cells was also investigated by the researchers. They were able to show that these LNPs could specifically transfect antigen-presenting cells in the spleen, which is a necessary step for eliciting strong immune responses.

Han said, “This finding opens up new possibilities for developing mRNA-based vaccines that can precisely target and activate the immune system, potentially leading to more effective and long-lasting immunity against various diseases.”

Mitchell and the group are concentrating on even more accurate targeting, especially in the lungs, as they work to improve their platform.

We’re now working on guiding our vehicles past the initial barrier of blood vessels to reach deeper into lung tissue. It’s a bit like programming our delivery system to navigate through increasingly complex security layers.”

Michael Mitchell, Associate Professor and Director, Department of Bioengineering in the School of Engineering and Applied Science, University of Pennsylvania

Source:
Journal reference:

Han, X., et al. (2024) Fast and facile synthesis of amidine-incorporated degradable lipids for versatile mRNA delivery in vivo. Nature Chemistry. doi.org/10.1038/s41557-024-01557-2

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