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
Annual blood test could detect cancer earlier and save lives
A single blood test, designed to pick up chemical signals indicative of the presence of many different types of cancer, could potentially thwart progression to advanced disease while the malignancy is still at an early [...]
How the FDA opens the door to risky chemicals in America’s food supply
Lining the shelves of American supermarkets are food products with chemicals linked to health concerns. To a great extent, the FDA allows food companies to determine for themselves whether their ingredients and additives are [...]
Superbug crisis could get worse, killing nearly 40 million people by 2050
The number of lives lost around the world due to infections that are resistant to the medications intended to treat them could increase nearly 70% by 2050, a new study projects, further showing the [...]
How Can Nanomaterials Be Programmed for Different Applications?
Nanomaterials are no longer just small—they are becoming smart. Across fields like medicine, electronics, energy, and materials science, researchers are now programming nanomaterials to behave in intentional, responsive ways. These advanced materials are designed [...]
Microplastics Are Invading Our Arteries, and It Could Be Increasing Your Risk of Stroke
Higher levels of micronanoplastics were found in carotid artery plaque, especially in people with stroke symptoms, suggesting a potential new risk factor. People with plaque buildup in the arteries of their neck have been [...]
Gene-editing therapy shows early success in fighting advanced gastrointestinal cancers
Researchers at the University of Minnesota have completed a first-in-human clinical trial testing a CRISPR/Cas9 gene-editing technique to help the immune system fight advanced gastrointestinal (GI) cancers. The results, recently published in The Lancet Oncology, show encouraging [...]
Engineered extracellular vesicles facilitate delivery of advanced medicines
Graphic abstract of the development of VEDIC and VFIC systems for high efficiency intracellular protein delivery in vitro and in vivo. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-59377-y. https://www.nature.com/articles/s41467-025-59377-y Researchers at Karolinska Institutet have developed a technique [...]
Brain-computer interface allows paralyzed users to customize their sense of touch
University of Pittsburgh School of Medicine scientists are one step closer to developing a brain-computer interface, or BCI, that allows people with tetraplegia to restore their lost sense of touch. While exploring a digitally [...]
Scientists Flip a Gut Virus “Kill Switch” – Expose a Hidden Threat in Antibiotic Treatment
Scientists have long known that bacteriophages, viruses that infect bacteria, live in our gut, but exactly what they do has remained elusive. Researchers developed a clever mouse model that can temporarily eliminate these phages [...]
Enhanced Antibacterial Polylactic Acid-Curcumin Nanofibers for Wound Dressing
Background Wound healing is a complex physiological process that can be compromised by infection and impaired tissue regeneration. Conventional dressings, typically made from natural fibers such as cotton or linen, offer limited functionality. Nanofiber [...]
Global Nanomaterial Regulation: A Country-by-Country Comparison
Nanomaterials are materials with at least one dimension smaller than 100 nanometres (about 100,000 times thinner than a human hair). Because of their tiny size, they have unique properties that can be useful in [...]
Pandemic Potential: Scientists Discover 3 Hotspots of Deadly Emerging Disease in the US
Virginia Tech researchers discovered six new rodent carriers of hantavirus and identified U.S. hotspots, highlighting the virus’s adaptability and the impact of climate and ecology on its spread. Hantavirus recently drew public attention following reports [...]
Studies detail high rates of long COVID among healthcare, dental workers
Researchers have estimated approximately 8% of Americas have ever experienced long COVID, or lasting symptoms, following an acute COVID-19 infection. Now two recent international studies suggest that the percentage is much higher among healthcare workers [...]
Melting Arctic Ice May Unleash Ancient Deadly Diseases, Scientists Warn
Melting Arctic ice increases human and animal interactions, raising the risk of infectious disease spread. Researchers urge early intervention and surveillance. Climate change is opening new pathways for the spread of infectious diseases such [...]
Scientists May Have Found a Secret Weapon To Stop Pancreatic Cancer Before It Starts
Researchers at Cold Spring Harbor Laboratory have found that blocking the FGFR2 and EGFR genes can stop early-stage pancreatic cancer from progressing, offering a promising path toward prevention. Pancreatic cancer is expected to become [...]
Breakthrough Drug Restores Vision: Researchers Successfully Reverse Retinal Damage
Blocking the PROX1 protein allowed KAIST researchers to regenerate damaged retinas and restore vision in mice. Vision is one of the most important human senses, yet more than 300 million people around the world are at [...]
