Improved miRNA Delivery method
Artificial regulatory RNA increased accuracy
Kirill Stasevich, CompulentaWhen RNA interference was discovered in 1998, they immediately thought about its practical application.
The essence of this molecular mechanism boils down to the following: small RNA molecules appear in the cell, which selectively suppress protein synthesis on some matrix RNAs. The matrix RNA itself, under the action of interfering RNAs, either simply falls silent, or is cut with the help of a special enzyme. The appearance of small RNAs is controlled by a complex molecular complex; the whole process is quite complicated, but we will not go into its subtleties now.
It is important that researchers suddenly saw in this RNA interference the possibility of point regulation of genes. And everyone immediately thought that with the use of regulatory RNAs, various diseases can be treated: for example, by blocking the activity of cancer genes with the help of artificial regulatory RNAs, it would be possible to suppress tumor growth. However, scientists quickly encountered the usual problem: how to deliver a large number of interfering RNAs (mRNAs) to the exact address so that these RNAs do not damage healthy tissues and organs?
The efficiency of delivery could be improved with the help of lipid microcapsules, which would carry a load of RNA inside themselves. Such experiments have been repeatedly performed, including in the laboratory of Daniel G. Anderson at the Massachusetts Institute of Technology (USA). In a new paper published in the journal PNAS, Mr. Anderson and colleagues describe how to make such particles even more effective, selective and safe (Dong et al., Lipopeptide nanoparticles for potential and selective siRNA delivery in rodents and nonhuman primates).
In general, these particles resemble the same lipid bubble with RNA molecules inside, but only now the lipid molecules have been linked to amino acids looking at the outside. The RNAs themselves are wrapped inside with a large number of lipopeptide molecules, cholesterol is embedded in the membrane, and everything together is also wrapped in a polymer polyethylene glycol for stabilization.
Figure from the article in PNAS – VM
The authors were able to program the behavior of the particles by changing the external amino acids and the way they attach to the lipid molecule: through an aldehyde group, acrylic or epoxy. It was possible to simulate something similar to natural lipoproteins, which transport lipids to the liver and whose behavior is largely determined by a set of proteins. Lipoids with regulatory RNAs were set up so that they were also sent to the liver and stopped the synthesis of one of the blood clotting factors there, and the effectiveness of purposefully disabling the gene in this case turned out to be five times higher than with conventional methods of mRNA delivery.
In another experiment, an attempt was made to turn off the synthesis of a tumor suppressor, which is synthesized not only in the liver, but also in other tissues and organs. And it turned out that the new lipoids blocked the synthesis exactly at the address, almost without touching other tissues.
Lipid particles delivered regulatory RNA (green) to the cells. (Photos of the authors of the work.)
Finally, in experiments on monkeys, scientists were able to suppress the synthesis of transthyretin, which is associated with diseases such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy.
Now researchers are faced with the following task: it is necessary to check whether it is possible to set up RNA-lipid particles for delivery to other organs with the same accuracy that was achieved for the liver, and also to trace what happens to this RNA later, when it has done its job. If the expectations are met, we will finally have an accurate and effective tool that allows us to regulate the activity of genes for medical purposes.
Prepared based on MIT News: Better RNA interference, inspired by nature.
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