To keep the immune system off guard, Zhang and
Hu set out to disguise the particles in membranes
from circulating red blood cells.
Early experiments were nightmarish. “The
lab was just setting up. We didn’t have a lot of
resources,” Hu recalls. He needed blood from
mice, but the group didn’t yet have approval
to purchase animals. The researchers turned
to neighboring labs. “We’d tell them, ‘If you’re
going to kill those mice, can we take some of their
blood?’ ” Hu says.
Drawing blood from the animals was not easy
for Hu and coworkers, who were used to dealing
with chemicals and polymers. “All of a sudden,
we were taking these dead mice and sticking a
syringe into the heart to take their blood,” he says.
At first “we got very little.” Mouse blood, the team
learned, clots quickly.
With practice, the researchers were soon collecting a milliliter of blood from each mouse. Hu
separated out the red blood cells, stripped their
membranes, then nudged the membrane pieces
Each milliliter of blood contained some
5 billion red blood cells, and a cut-up membrane
from a single red blood cell could coat several
thousand nanoparticles. Injected into live mice,
the hybrid particles spread through the body
and stayed intact for three days. “We kind of got
lucky,” Hu says of those early efforts.
Soon after, a team at the Houston Methodist
Research Institute in Texas reported a similar
feat, coating nanoparticles with the membranes
of white blood cells of the immune system. Like
the UC San Diego group, the Houston research-
ers felt they were going out on a limb by mixing
synthetic particles with parts of live cells. “People
in the nano field were telling me I was crazy,” says
nanoengineer Ennio Tasciotti, the team leader.
Tasciotti’s group covered its particles with
membranes from various kinds of white blood
cells, or leukocytes. The particles “were look-alikes of a leukocyte,” Tasciotti quips. Leukocytes
are expert scavengers that take “the VIP path” to
go wherever the infection or foreign invader is,
Tasciotti says. When leukocytes touch down on
the surface of blood vessels, the lining opens to
allow the cells to enter.
The “leukolike” particles could avoid attack by
macrophages, which gobble up foreign substances,
the researchers showed in a set of experiments
published in 2012. The researchers used the particles to carry a cancer drug across a layer of endothelial cells, which make up the lining of blood vessels.
Tasciotti’s team has since replaced synthetic
nanoparticles with natural ones, made from
thin sheets of fat cells that form spherical blobs
called liposomes, the researchers reported in
2016 in Nature Materials. With no artificial parts,
Tasciotti says, his leukocyte-coated liposomes, or
“leukosomes,” so far tested in lab animals, could
face an easier path to FDA approval for use in
Even when the leukosomes weren’t carrying a
drug, they interacted with living tissues in helpful
ways, Tasciotti says. In 2017 in Nanoscale, he and
colleagues reported that leukosomes could relieve
inflammation and help repair damaged tissue in
the gastrointestinal tract of mice that had a form
of inflammatory bowel disease.
While the Houston team and other labs were tinkering with nanoagents to deliver cancer drugs
and heal tissues, Zhang ventured into infectious
As he and Hu brainstormed uses for their
membrane-coated particles, they came upon a
key realization. Unlike PEG-coated nanoparticles that just sneak through the body, Zhang and
Hu’s nanoparticles are enclosed within biological
membranes from cells that normally interact with
tissues and with a plethora of chemical messengers and molecules in the body. Perhaps, then,
these interactive membrane-coated particles
could put up a fight against toxins, the biological
weapons of pathogens.
In 2011, as antibiotic resistance was gaining recognition as a serious public health threat, Zhang
learned about pore-forming toxins. These small
proteins are released by many pathogens, including MRSA, the strain of Staphylococcus aureus that
Diversion Toxins (purple) kill blood cells by attaching to and puncturing the cells’
surface (left). Nanosponges protect the blood cells by ensnaring the toxins (right).
Toxins destroy blood cells Nanosponges protect blood cells
The two nanosponges in
this electron microscopy
image are coated with
membranes from red