Researchers unlock safer RNA therapies for inflammatory diseases

Lipid nanoparticles (LNPs) are tiny fat bubbles that are used to deliver medicines, genes, and RNA into cells. However, in some cases LNPs can cause harmful inflammation as a result of the process of RNA delivery. Now, two new solutions can help alleviate inflammation while still getting RNA where it needs to be in the cell. One discovery finds that inflammation could be reduced with the addition of a unique biodegradable lipid to the treatment; another solution identifies a common drug, called thiodigalactoside (TG), which blocks inflammation when added to the LNP. The study is published in Nature Nanotechnology.

“For patients with inflammatory diseases like ARDS, heart attack, or stroke, our solutions—a new lipid and a galectin-blocking drug—make RNA therapies safer,” says study co-author Jacob Brenner, an assistant professor of pulmonary, allergy, and critical care at the Perelman School of Medicine.

LNPs enter cells with the help of endosomes, tiny sacs which help direct material entering cells to the right places. The research team found that when LNPs are delivering their “load” of RNA, the endosomes rupture like a burst balloon, allowing harmful substances to leak out and spark immune responses. These holes are detected by proteins called galectins, which drive inflammation.

Researchers found that adding a special fat molecule, 4A3-SC8, makes smaller holes that the cell can quickly patch up, reducing inflammation while keeping RNA delivery effective. In other words, the endosome springs a leak and the fat molecule can fix it. They also discovered that a readily available but uncommon drug called thiodigalactoside (TG) can block inflammation when added to LNPs.

“By designing LNPs that cause less damage and block inflammation pathways, we can expand RNA treatments to conditions like ARDS, heart attack, and stroke, where inflammation is a major challenge,” Brenner says.

Read more at Penn Medicine News.