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NEW NANOPARTICLE THERAPIES TARGET TWO MAJOR KILLERS  
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Robert F. Service
March 28, 2025
Science
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_ Particles loaded with RNA reverse symptoms of respiratory failure
and atherosclerosis in mice _

New nanoparticles aim to reverse respiratory failure and
atherosclerosis., Peter Allen/Second Bay Studios

 

SAN DIEGO—RNA vaccines packaged in tiny fatty containers called
nanoparticles saved tens of millions from COVID-19. Now, 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. Won Hyuk Suh, a biomaterials expert at the University
of New Hampshire who organized the scientific session at the ACS
meeting, notes that the findings are preliminary but calls them
“very interesting and promising.” They were posted on the bioRxiv
preprint server
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January.

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.

Zhou acknowledges that “there are still a lot of barriers to
overcome.” Past studies, for example, have shown that nanoparticles
that seem to work in mice sometimes trigger immune reactions in larger
animals, including humans. But Suh thinks the new nanoparticles may
sidestep that problem because they’re “very well defined” and
thus less likely to incorporate immune-triggering components.

Another hurdle, Zhou notes, is that restoring healthy function to
large tissues would require far larger RNA doses than those used in
vaccines, raising the odds of side effects. However, he adds, doctors
might be able to get around that simply by giving several shots, each
with a low dose. “We can give this repeatedly,” Zhou says. If
these early results hold up, millions of people may stand to benefit.

doi: 10.1126/science.zqbtd4b

_BOB SERVICE is a news reporter for Science in Portland,
Oregon, covering chemistry, materials science, and energy stories._

_SCIENCE has been at the center of important scientific discovery
since its founding in 1880—with seed money from Thomas Edison.
Today, Science continues to publish the very best in research across
the sciences, with articles that consistently rank among the most
cited in the world. In the last half century
alone, Science published:_

* _The entire human genome for the first time_
* _Never-before seen images of the Martian surface_
* _The first studies tying AIDS to human immunodeficiency virus_

_A trailblazer in online publishing as well, the Science family of
publications has grown to include online journals Science
Translational Medicine, Science Signaling, Science
Immunology, Science Robotics and the open access journal Science
Advances._

__

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