Nanoparticles, (Liquid Nanoparticles - LNPs) were used in Covid vaccines. Now the researchers are trying to use similar nanoparticles to fight two other major killers, respiratory failure caused by lung infections such as flu and the atherosclerosis that leads to heart attacks and strokes. In both conditions, the endothelial cells that line blood vessels malfunction, turning down key genes. New research presented at the American Chemical Society (ACS) meeting here this week shows that nanoparticles carrying a payload of RNA can ramp the genes back up, promising to address the diseases at their root.
Nanoparticles are a familiar tool in medicine, but the scheme to use them to treat endothelial cells is “excellent work,” says Robert Langer, a nanoparticle therapy pioneer at the Massachusetts Institute of Technology.
Atherosclerosis and respiratory failure due to infections such as flu might seem to have little in common. But both involve inflammation of endothelial cells. In the case of acute respiratory distress syndrome (ARDS), the inflammation causes endothelial cells in capillaries adjacent to the lung’s tiny air sacs, or alveoli, to reduce levels of KLF2, a protein “transcription factor” that helps regulate a series of other genes needed for healthy cell function. As a result, these capillaries become porous, leaking fluid into the alveoli, which prevents oxygen from diffusing into the blood, often killing patients.
In atherosclerosis, an initial buildup of fatty deposits called plaques disrupts the normal smooth flow of blood, causing nearby epithelial cells to produce less of a lipid-metabolizing enzyme called PLPP3. That drives further inflammation and plaque buildup that can block arteries and trigger a heart attack or break off and cause a stroke.
Existing treatments, such as mechanical respirators for ARDS patients and cholesterol-lowering medications for atherosclerosis, don’t directly address the epithelial cell dysfunction. So, several years ago, researchers led by Matthew Tirrell, a chemical engineer at the University of Chicago, set out to see whether they could design nanoparticles to deliver copies of messenger RNAs for either KLF2 or PPLP3 to the errant cells. Their hope was that the messenger RNA messages would be read by the cells’ protein-building machinery and churn out copies of the proteins, restoring healthy function to diseased cells.
To target the nanoparticles to the cells, Tirrell’s team equipped them with a short protein fragment, or peptide, designed to home in on VCAM1, a cell-surface receptor found on inflamed epithelial cells.
At the ACS meeting, Zhengjie Zhou, a postdoc in Tirrell’s lab, reported that in the test tube, the particles homed in on dysfunctional epithelial cells while leaving normal epithelial cells alone. Their RNA cargo turned up production of KLF2 and PPLP3, as hoped. And in mouse models of ARDS and atherosclerosis, the nanoparticles increased levels of these desired proteins and eased signs of disease.
In mice infected with the H1N1 influenza virus, for example, the nanoparticles reduced the severity of lung damage and immune activity indicative of ARDS by roughly half. In the atherosclerosis tests, the treated animals showed an 83% reduction in vascular inflammation at the site of plaque buildup. Their plaques also showed signs of stabilizing and becoming less prone to break apart and trigger a heart attack or stroke.
Note that there will be barriers to overcome as nanoparticles that seem to work in mice can trigger immune reaction in large animals including humans. Also with humans a larger doses than delivered in the vaccines could be required but this can be easily addressed.
Nanoparticles are a familiar tool in medicine, but the scheme to use them to treat endothelial cells is “excellent work,” says Robert Langer, a nanoparticle therapy pioneer at the Massachusetts Institute of Technology.
Atherosclerosis and respiratory failure due to infections such as flu might seem to have little in common. But both involve inflammation of endothelial cells. In the case of acute respiratory distress syndrome (ARDS), the inflammation causes endothelial cells in capillaries adjacent to the lung’s tiny air sacs, or alveoli, to reduce levels of KLF2, a protein “transcription factor” that helps regulate a series of other genes needed for healthy cell function. As a result, these capillaries become porous, leaking fluid into the alveoli, which prevents oxygen from diffusing into the blood, often killing patients.
In atherosclerosis, an initial buildup of fatty deposits called plaques disrupts the normal smooth flow of blood, causing nearby epithelial cells to produce less of a lipid-metabolizing enzyme called PLPP3. That drives further inflammation and plaque buildup that can block arteries and trigger a heart attack or break off and cause a stroke.
Existing treatments, such as mechanical respirators for ARDS patients and cholesterol-lowering medications for atherosclerosis, don’t directly address the epithelial cell dysfunction. So, several years ago, researchers led by Matthew Tirrell, a chemical engineer at the University of Chicago, set out to see whether they could design nanoparticles to deliver copies of messenger RNAs for either KLF2 or PPLP3 to the errant cells. Their hope was that the messenger RNA messages would be read by the cells’ protein-building machinery and churn out copies of the proteins, restoring healthy function to diseased cells.
To target the nanoparticles to the cells, Tirrell’s team equipped them with a short protein fragment, or peptide, designed to home in on VCAM1, a cell-surface receptor found on inflamed epithelial cells.
At the ACS meeting, Zhengjie Zhou, a postdoc in Tirrell’s lab, reported that in the test tube, the particles homed in on dysfunctional epithelial cells while leaving normal epithelial cells alone. Their RNA cargo turned up production of KLF2 and PPLP3, as hoped. And in mouse models of ARDS and atherosclerosis, the nanoparticles increased levels of these desired proteins and eased signs of disease.
In mice infected with the H1N1 influenza virus, for example, the nanoparticles reduced the severity of lung damage and immune activity indicative of ARDS by roughly half. In the atherosclerosis tests, the treated animals showed an 83% reduction in vascular inflammation at the site of plaque buildup. Their plaques also showed signs of stabilizing and becoming less prone to break apart and trigger a heart attack or stroke.
Note that there will be barriers to overcome as nanoparticles that seem to work in mice can trigger immune reaction in large animals including humans. Also with humans a larger doses than delivered in the vaccines could be required but this can be easily addressed.
