MADRID, Dec 27 (EUROPA PRESS) -Researchers at the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG), in Germany, together with researchers from the biopharmaceutical company AstraZeneca, who were investigating where and how mRNA is delivered inside the cell have discovered that it uses a gateway unexpected, as published in the 'Journal of Cell Biology'.In recent years, ribonucleic acid (RNA) has emerged as a powerful tool for the development of new therapies.It is used to copy the genetic information contained in our hereditary material, deoxyribonucleic acid (DNA), and then serves as a template to build proteins, the building blocks of life.The delivery of RNA to cells remains a major challenge for the development of novel therapies in a wide range of diseases.DNA (deoxyribonucleic acid) contains the genetic information necessary for the development and maintenance of life.This information is communicated by messenger ribonucleic acid (mRNA) to make proteins.MRNA-based therapies have the potential to meet the unmet needs of a wide variety of diseases, including cancer and cardiovascular disease.The mRNA can be delivered to cells to trigger the production, degradation, or modification of a target protein, something impossible with other approaches.It can be embedded in lipid nanoparticles (LNP) - small bubbles of fat - that protect the mRNA and transport it into cells.However, this process is not easy, because the mRNA has to cross the membrane before reaching its place of action inside the cell, the cytoplasm.Researchers from the team of MPI-CBG director, Marino Zerial, are experts in visualizing the pathways of entry of molecules into the cell, such as mRNA, with high-resolution microscopes.They partnered with AstraZeneca scientists who provided researchers with prototypes of lipid nanoparticles that they had developed for therapeutic approaches to follow mRNA within the cell."To be delivered, the mRNA has to make a long journey. Enclosed in the bubble of the fatty LNP, it has to enter the cell first - explains Marino Zerial -. The LNPs reach the cell surface, where they bind to the cells. Receptors, which are then inserted into specialized compartments enclosed in the membrane, called endosomes. ""At this point, the mRNA is inside the cells but surrounded by two barriers, the fat bubble and the endosome wall or, more correctly, the membrane --he continues -. The challenge of the mRNA is to escape from both barriers to reach the cytoplasm, where it serves as a template for making proteins. We know that only a small fraction of RNA molecules are capable of escaping into the cytoplasm. "Internalized cargo molecules, such as LNPs, are first transported to "early" endosomes.These are logistics centers that distribute cargo molecules to various destinations in the cell.They receive the molecules to the cell surface or degrade them in late endosomes and lysosomes.Until now it was thought that mRNA escaped from late endosomes by taking advantage of their highly acidic content."With single-molecule microscopy techniques we were able to visualize for the first time the mRNA in the LNP within the endosomes of the cells," explains Prasath Paramasivam, first author of the study. "We also captured the actual escape of the mRNA, which occurred in the tubules of the recycling endosomes, which are only slightly acidic. ""Our results imply that delivering LNP mRNA to late endosomes is counterproductive for delivery and only increases cellular toxicity," Zerial adds.These findings help to understand in more detail the escape mechanism of mRNA from endosomes.Marino Zerial summarizes noting that "the mRNA delivery system by NLP requires high doses due to the low efficiency of endosomal escape. Knowing where mRNA goes and how it can escape from endosomes allows us to develop better vehicles for more efficient delivery, with a lower dose. We can improve the mRNA delivery system so that it can be used in therapeutic applications, for example in the treatment of cancer, "he concludes.© 2021 Europa Press.The redistribution and redistribution of all or part of the contents of this website without your prior and express consent is expressly prohibited.