Recent research has uncovered a breakthrough in repairing lung damage caused by respiratory viruses. Researchers have discovered that delivering VEGFA via lipid nanoparticles can significantly repair damaged blood vessels, similar to plumbing repairs. This method has been validated in animal models and offers promising insights into treating respiratory virus damages, enhancing oxygen delivery, and reducing lung inflammation and scarring.
The lungs and their vasculature in the human body are like a building with an intricate plumbing system. The blood vessels of the lungs transport blood and nutrients for oxygen delivery and carbon dioxide removal. Just like how pipes can get rusty or clogged, respiratory viruses like SARS-CoV-2 or influenza can interfere with this “plumbing system.”
In a recent study, researchers focused on the crucial role of vascular endothelial cells in lung repair. Their work, published in Science Translational Medicine and led by Andrew Vaughan of the University of Pennsylvania’s School of Veterinary Medicine, shows that by using techniques that deliver vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs), they were able to greatly enhance the repair of damaged blood vessels. This is similar to how plumbers patch sections of broken pipes and add new ones.
Advanced Research Findings
“While our lab and others have previously shown that endothelial cells are among the unsung heroes in repairing the lungs after viral infections like the flu, this tells us more about the story and sheds light on the molecular mechanisms at play,” said Vaughan, assistant professor of biomedical sciences at Penn Vet. Vaughan also stated, “Here we’ve identified and isolated pathways involved in repairing this tissue, delivered mRNA to endothelial cells, and consequently observed enhanced recovery of the damaged tissue. These findings hint at a more efficient way to promote lung recovery after diseases like COVID-19.”
In their research, the scientists discovered that VEGFA played a significant role in the regeneration process. This was based on their previous work where they had used single cell RNA sequencing to identify TGFBR2 as a major signaling pathway. The researchers observed that the absence of TGFBR2 inhibited the activation of VEGFA. This lack of signal resulted in reduced multiplication and renewal of blood vessel cells, which is essential for the exchange of oxygen and carbon dioxide in the lungs’ tiny air sacs.
“We’d known there was a link between these two pathways, but this motivated us to see if delivering VEGFA mRNA into endothelial cells could improve lung recovery after disease-related injury,” said the first author Gan Zhao, a postdoctoral researcher in the Vaughan Lab.
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Innovative Delivery Methods
The Vaughan Lab contacted Michael Mitchell of the School of Engineering and Applied Science to explore the feasibility of delivering the mRNA cargo using LNPs.
“LNPs have been great for vaccine delivery and have proven incredibly effective delivery vehicles for genetic information. But the challenge here was to get the LNPs into the bloodstream without them heading to the liver, which is where they tend to congregate as its porous structure lends favor to substances passing from the blood into hepatic cells for filtration,” said Mitchell, an associate professor of bioengineering at Penn Engineering and a coauthor of the paper. “So, we had to devise a way to specifically target the endothelial cells in the lungs.” Mitchell added.
Xue said: “We’ve seen evidence in the literature suggesting it’s doable, but the systems we’d seen are made up of positively charged lipids which were too toxic,”. “This led me to developing an ionizable lipid that’s not positively charged when it enters the bloodstream but gets charged when it gets to the endothelial cells, thereby releasing the mRNA” Xue added.
The researchers found that their LNPs were effective in transporting VEGFA into endothelial cells, resulting in a significant improvement in vascular recovery in animal models. The treatment led to improved oxygen levels and better weight recovery compared to the control group in some of the animal models. The treated mice also showed lower levels of certain markers in their lung fluid, indicating less lung inflammation, and their lungs had less damage and scarring, with more healthy blood vessels.
Vaughan said: “Although we went in hoping for this outcome, it was a real thrill to see how effective, safe, and efficiently this all panned out, so we’re looking forward to testing this delivery platform for other cell types in the lung, and it will be important to evaluate whether TGFB signaling is important in other injury contexts including chronic conditions like emphysema and COPD,”. “With this proof-of-concept being well validated, we’re sure that we’ll pave the way for new mRNA-based strategies for treating lung injury.”
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References:
1. Zhao, G., Xue, L., Weiner, A. I., Gong, N., Adams-Tzivelekidis, S., Wong, J., … & Vaughan, A. E. (2024). TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue. Science Translational Medicine, 16(732), eadg6229.
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