Recent research reveals a breakthrough in lung repair, showing how delivering VEGFA via lipid nanoparticles can significantly repair damaged blood vessels, akin to plumbing repairs. This method, validated in animal models, offers promising insights into treating respiratory virus damages, enhancing oxygen delivery, and reducing lung inflammation and scarring.
In the human body, the lungs and their vasculature can be likened to a building with an intricate plumbing system. The lungs' blood vessels are the pipes essential for transporting blood and nutrients for oxygen delivery and carbon dioxide removal. Much like how pipes can get rusty or clogged, disrupting normal water flow, damage from respiratory viruses, like SARS-CoV-2 or influenza, can interfere with this "plumbing system."
In a recent study, researchers looked at the critical role of vascular endothelial cells in lung repair. Their work, published in Science Translational Medicine, was led by Andrew Vaughan of the University of Pennsylvania's School of Veterinary Medicine and shows that, by using techniques that deliver vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs), that they were able to greatly enhance modes of repair for these damaged blood vessels, much like 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," says Vaughan, assistant professor of biomedical sciences at Penn Vet. "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."
They found VEGFA's involvement in this recovery, while building on work in which they used single cell RNA sequencing to identify transforming growth factor beta receptor 2 (TGFBR2) as a major signaling pathway. The researchers saw that when TGFBR2 was missing it stopped the activation of VEGFA. This lack of signal made the blood vessel cells less able to multiply and renew themselves, which is vital for the exchange of oxygen and carbon dioxide in the tiny air sacs of the lungs.
"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," says first author Gan Zhao, a postdoctoral researcher in the Vaughan Lab.
Innovative Delivery Methods
The Vaughan Lab then reached out to Michael Mitchell of the School of Engineering and Applied Science, whose lab specializes in LNPs, to see if delivery of this mRNA cargo would be feasible.
"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," says 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."
Lulu Xue, a postdoctoral researcher in the Mitchell Lab and a co-first author of the paper, explains that they engineered the LNP to have an affinity for lung endothelial cells, this is known as extra hepatic delivery, going beyond the liver.
"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," Xue says. "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."
Their LNPs proved effective in delivering VEGFA into endothelial cells and as a result, the researchers saw a marked improvement in vascular recovery in their animal models. Within the animal models, the researchers saw improved oxygen levels, and in some, the treatment helped them recover their weight better than the control group. These treated mice also had less lung inflammation, shown by lower levels of certain markers in their lung fluid, and their lungs showed less damage and scarring, with more healthy blood vessels.
"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," Vaughan says. "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."
Reference: "TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue" by Gan Zhao, Lulu Xue, Aaron I. Weiner, Ningqiang Gong, Stephanie Adams-Tzivelekidis, Joanna Wong, Maria E. Gentile, Ana N. Nottingham, Maria C. Basil, Susan M. Lin, Terren K. Niethamer, Joshua M. Diamond, Christian A. Bermudez, Edward Cantu, Xuexiang Han, Yaqi Cao, Mohamad-Gabriel Alameh, Drew Weissman, Edward E. Morrisey, Michael J. Mitchell and Andrew E. Vaughan, 31 January 2024, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adg6229
Andrew Vaughan is an assistant professor in the Department of Biomedical Sciences at the University of Pennsylvania School of Veterinary Medicine.
Michael Mitchell is an associate professor in the Department of Bioengineering in the School of Engineering and Applied Science and the director of the Lipid Nanoparticle Synthesis Core at the Penn Institute for RNA Innovation at the University of Pennsylvania.
Gan Zhao is a postdoctoral researcher in the Vaughn Lab at Penn Vet.
Lulu Xue is a postdoctoral researcher in the Mitchell Lab at Penn Engineering.
Other authors include Stephanie Adams-Tzivelekidis, Maria E. Gentile, Aaron I. Weiner, and Joanna Wong from Penn Vet; Ningqiang Gong and Xuexiang Han from Penn Engineering; and Mohamad-Gabriel Alameh, Maria C. Basil, Christian A. Bermudez, Edward Cantu, Yaqi Cao, Joshua M. Diamond, Susan M. Lin, Edward E. Morrisey, Terren K. Niethamer, Ana N. Nottingham, and Drew Weissman in the Perelman School of Medicine at Penn.
This work was supported by the National Institutes of Health (grants R01HL153539 and R01HL164350 and award DP2 TR002776, the Margaret Q. Landenberger Foundation, a Burroughs Wellcome Fund Career Award at the Scientific Interface; and the National Science Foundation (Award CBET-2145491).
News
Two New Books From Frank Boehm, NA Founder – To be Released Dec. 2025
Molecular Manufacturing: The Future of Nanomedicine This book explores the revolutionary potential of atomically precise manufacturing technologies to transform global healthcare, as well as practically every other sector across society. This forward-thinking volume examines [...]
What could the future of nanoscience look like?
Society has a lot to thank for nanoscience. From improved health monitoring to reducing the size of electronics, scientists’ ability to delve deeper and better understand chemistry at the nanoscale has opened up numerous [...]
Scientists Melt Cancer’s Hidden “Power Hubs” and Stop Tumor Growth
Researchers discovered that in a rare kidney cancer, RNA builds droplet-like hubs that act as growth control centers inside tumor cells. By engineering a molecular switch to dissolve these hubs, they were able to halt cancer [...]
Platelet-inspired nanoparticles could improve treatment of inflammatory diseases
Scientists have developed platelet-inspired nanoparticles that deliver anti-inflammatory drugs directly to brain-computer interface implants, doubling their effectiveness. Scientists have found a way to improve the performance of brain-computer interface (BCI) electrodes by delivering anti-inflammatory drugs directly [...]
After 150 years, a new chapter in cancer therapy is finally beginning
For decades, researchers have been looking for ways to destroy cancer cells in a targeted manner without further weakening the body. But for many patients whose immune system is severely impaired by chemotherapy or radiation, [...]
Older chemical libraries show promise for fighting resistant strains of COVID-19 virus
SARS‑CoV‑2, the virus that causes COVID-19, continues to mutate, with some newer strains becoming less responsive to current antiviral treatments like Paxlovid. Now, University of California San Diego scientists and an international team of [...]
Lower doses of immunotherapy for skin cancer give better results, study suggests
According to a new study, lower doses of approved immunotherapy for malignant melanoma can give better results against tumors, while reducing side effects. This is reported by researchers at Karolinska Institutet in the Journal of the National [...]
Researchers highlight five pathways through which microplastics can harm the brain
Microplastics could be fueling neurodegenerative diseases like Alzheimer's and Parkinson's, with a new study highlighting five ways microplastics can trigger inflammation and damage in the brain. More than 57 million people live with dementia, [...]
Tiny Metal Nanodots Obliterate Cancer Cells While Largely Sparing Healthy Tissue
Scientists have developed tiny metal-oxide particles that push cancer cells past their stress limits while sparing healthy tissue. An international team led by RMIT University has developed tiny particles called nanodots, crafted from a metallic compound, [...]
Gold Nanoclusters Could Supercharge Quantum Computers
Researchers found that gold “super atoms” can behave like the atoms in top-tier quantum systems—only far easier to scale. These tiny clusters can be customized at the molecular level, offering a powerful, tunable foundation [...]
A single shot of HPV vaccine may be enough to fight cervical cancer, study finds
WASHINGTON -- A single HPV vaccination appears just as effective as two doses at preventing the viral infection that causes cervical cancer, researchers reported Wednesday. HPV, or human papillomavirus, is very common and spread [...]
New technique overcomes technological barrier in 3D brain imaging
Scientists at the Swiss Light Source SLS have succeeded in mapping a piece of brain tissue in 3D at unprecedented resolution using X-rays, non-destructively. The breakthrough overcomes a long-standing technological barrier that had limited [...]
Scientists Uncover Hidden Blood Pattern in Long COVID
Researchers found persistent microclot and NET structures in Long COVID blood that may explain long-lasting symptoms. Researchers examining Long COVID have identified a structural connection between circulating microclots and neutrophil extracellular traps (NETs). The [...]
This Cellular Trick Helps Cancer Spread, but Could Also Stop It
Groups of normal cbiells can sense far into their surroundings, helping explain cancer cell migration. Understanding this ability could lead to new ways to limit tumor spread. The tale of the princess and the [...]
New mRNA therapy targets drug-resistant pneumonia
Bacteria that multiply on surfaces are a major headache in health care when they gain a foothold on, for example, implants or in catheters. Researchers at Chalmers University of Technology in Sweden have found [...]
Current Heart Health Guidelines Are Failing To Catch a Deadly Genetic Killer
New research reveals that standard screening misses most people with a common inherited cholesterol disorder. A Mayo Clinic study reports that current genetic screening guidelines overlook most people who have familial hypercholesterolemia, an inherited disorder that [...]
