S19B
iologists studying extracellular RNA
(exRNA) — and the tiny spherical struc-
tures known as exosomes that shuttle
this genetic information from cell to
cell — typically focus on mammals.
As long ago as the 1960s, however, scientists
found that plant cells also generate vesicles
that carry cargo out of the cell membrane.
But for decades, these botanical observations
were largely forgotten.
Plant biologist Hailing Jin at the University of
California, Riverside, is trying to revive the field
to work out how plants send cellular messages.
She has found evidence that plants do this, in
part, to thwart their fungal enemies. She is now
designing fungicides that are based on exRNA.
Her team has engineered tomato plants to
release exRNA that can silence the genes of the
fungus Botrytis cinerea^1 , which causes the grey
mould disease that destroys millions of fruit,
vegetable and flower plants every year. “The
plants are much healthier” than those that lack
this special twist, Jin says. When sprayed with
the fungus, the leaves of engineered plants
remain green and vibrant, whereas their nor-
mal counterparts develop splotchy leaves that
are darkened and dying.
In 2013, her group found evidence that
exosomes facilitate ‘crosstalk’ between plants
and fungi^2. The researchers suggested that
B. cinerea releases small RNAs that silence
immunity genes in the model organism
Arabidopsis thaliana. “Her 2013 paper was a
real landmark,” says Roger Innes, a biologist at
Indiana University in Bloomington. “It opened
up whole new directions in plant science.”
Jin’s lab has since shown that Arabidopsis
cells release extracellular vesicles that deliver
RNA into B. cinerea, and that this RNA silences
genes that are important in the fungus’s ability
to infect plants^3. And in a paper posted on the
preprint server bioRxiv^4 , biologists reported
that altering Arabidopsis so that the plants
release exRNA offers some protection against
a type of pathogenic bacteria. These results,
which have not been peer reviewed, are “really
shocking”, Innes says. “Bacteria don’t have aclassic RNA-interference pathway — so it has
to be incorporated into some novel pathway
that’s leading to gene silencing in bacteria.”
Jin says that although some scientists are
continuing to genetically modify vegetables
and fruits to fight destructive fungi and bac-
teria with exRNA, the lengthy and expensive
regulatory process for genetically modified
food means her team is pursuing a different
approach. It is instead designing antifungal
crop sprays that contain the silencing RNA.Other scientists have taken inspiration from
the exRNA communication seen in plants to
design human therapies. Huang-Ge Zhang, an
immunologist at the University of Louisville
School of Medicine in Kentucky, is trying to
mimic the RNA-shuttling vesicles found in
plants by extracting and repurposing cel-
lular components of fruits and vegetables.
He has shown that grapefruit juice contains
lipids — molecules that make up much of the
membrane of cells and exosomes — that can
be assembled into small shells that he calls
“exosome-like nanovectors”^5. Zhang and his
colleagues loaded these nanovectors with
anti-cancer drugs and gave them to mice with
tumours. They found that mice that received
this form of therapy lived for an average of
42.5 days, whereas mice treated with eitherempty nanovectors or with the chemotherapy
agent on its own lived for 20–30 days. Zhang
says that one of the advantages of encapsu-
lating drugs in this way is that the foods from
which they are derived are non-toxic and cheap.
Zhang has received more than US$1 million
from the US National Institutes of Health for
his work. He is currently collaborating with
researchers at Louisville’s James Graham Brown
Cancer Center on a clinical trial to test the use
of plant-derived vectors to deliver curcumin —
a component of the spice turmeric — to treat
colorectal cancer. Zhang is also exploring
whether ginger-derived vectors can be loaded
with RNA-based therapeutics. His projects have
attracted some commercial interest. Other
groups are also exploring whether plant-de-
rived nanovesicles can be used to deliver
cancer therapeutics.
Some scientists say, however, that Zhang’s
drug-shuttling structures can’t be called
exosome-like. They point out that even though
the structures are roughly the same size as
exosomes, and are built with lipid molecules,
that doesn’t mean the structures behave in the
same way. It’s not just their size that makes
exosomes special, says Clotilde Théry, who
studies exosome biology at the Curie Institute
in Paris. “Many extracellular vesicles or par-
ticles other than exosomes can display the
same range of size,” Théry explains, but they
don’t necessarily behave like exosomes. It is
unclear, for example, whether the nanovec-
tors can transmit payloads to cells in the same
way as some exosomes do. And the human
immune system might thwart plant-derived
nanovectors, rendering them useless.
Innes, for his part, is looking for more
evidence that exosomes are indeed involved
in RNA signalling. Circular cross-sections can
be seen near plant cells under a microscope,
but Innes wants to confirm that these shapes
are exosome spheres, and not just cylindrical
tubes. To do this, his group is creating ultra-
thin slices of plant cells and capturing an image
of each slice with an electron microscope. It
can then digitally recreate the 3D shape of the
tiny structures assumed to be exosomes. He’s
sure that plants do send out RNA signals, but
he wants to definitively show the form of the
structures that shuttle this genetic informa-
tion. “We know it works,” Innes says. “The big
question right now is how.”Roxanne Khamsi is a freelance science
journalist in Montreal, Canada. . Wang, M. et al. Nature Plants , ( ).
. Weiberg, A. et al. Science , – ( ).
. Cai, Q. et al. Science , – ( ).
. Singla-Rastogi, M. et al. Preprint at bioRxiv https://doi.
org/ . / ( ).
. Wang, Q. et al. Nature Commun. , ( ).
GETTYExtracellular RNA
outlook
Nature | Vo | June | S19Planting the seed of
RNA crosstalk
Studies hinting that plants and fungi exchange RNA
through extracellular vesicles are inspiring scientists
to develop ways to protect crops. By Roxanne KhamsiGrey mould affects fruits such as strawberries.Outlook exRNA Khamsi (plants) MA JR_sd.indd 19 6/8/20 12:44 PM
SciAm0820_OutlookTemplate.indd 19 6/8/20 1:06 PM