The programmable DNA nanorobot was modeled on the body’s own immune system in which white blood cells patrol the bloodstream for any signs of trouble. Image: Harvard University |
Researchers at the Wyss Institute for Biologically
Inspired Engineering at Harvard
University have developed
a robotic device made from DNA that could potentially seek out specific cell
targets within a complex mixture of cell types and deliver important molecular
instructions, such as telling cancer cells to self-destruct. Inspired by the
mechanics of the body’s own immune system, the technology might one day be used
to program immune responses to treat various diseases. The research findings
appear in Science.
Using the DNA origami method, in which complex 3D shapes
and objects are constructed by folding strands of DNA, Shawn Douglas, PhD, a
Wyss Technology Development Fellow, and Ido Bachelet, PhD, a former Wyss Postdoctoral
Fellow who is now an assistant professor in the Faculty of Life Sciences and
the Nano-Center at Bar-Ilan University in Israel, created a nanosized robot in
the form of an open barrel whose two halves are connected by a hinge. The DNA
barrel, which acts as a container, is held shut by special DNA latches that can
recognize and seek out combinations of cell-surface proteins, including disease
markers. When the latches find their targets, they reconfigure, causing the two
halves of the barrel to swing open and expose its contents, or payload. The
container can hold various types of payloads, including specific molecules with
encoded instructions that can interact with specific cell surface signaling
receptors.
Douglas and Bachelet used this system to deliver
instructions, which were encoded in antibody fragments, to two different types
of cancer cells—leukemia and lymphoma. In each case, the message to the cell
was to activate its “suicide switch”—a standard feature that allows
aging or abnormal cells to be eliminated. And since leukemia and lymphoma cells
speak different languages, the messages were written in different antibody
combinations.
This programmable nanotherapeutic approach was modeled on
the body’s own immune system in which white blood cells patrol the bloodstream
for any signs of trouble. These infection fighters are able to home in on
specific cells in distress, bind to them, and transmit comprehensible signals
to them to self-destruct. The DNA nanorobot emulates this level of specificity
through the use of modular components in which different hinges and molecular
messages can be switched in and out of the underlying delivery system, much as
different engines and tires can be placed on the same chassis. The programmable
power of this type of modularity means the system has the potential to one day
be used to treat a variety of diseases.
“We can finally integrate sensing and logical
computing functions via complex, yet predictable, nanostructures—some of the
first hybrids of structural DNA, antibodies, aptamers, and metal atomic
clusters—aimed at useful, very specific targeting of human cancers and T-cells,”
said George Church, PhD, a Wyss core faculty member and Professor of Genetics
at Harvard Medical School, who is principal investigator on the project.
Because DNA is a natural biocompatible and biodegradable material, DNA
nanotechnology is widely recognized for its potential as a delivery mechanism
for drugs and molecular signals. But there have been significant challenges to its
implementation, such as what type of structure to create; how to open, close,
and reopen that structure to insert, transport, and deliver a payload; and how
to program this type of nanoscale robot.
By combining several novel elements for the first time,
the new system represents a significant advance in overcoming these
implementation obstacles. For instance, because the barrel-shaped structure has
no top or bottom lids, the payloads can be loaded from the side in a single
step—without having to open the structure first and then reclose it. Also,
while other systems use release mechanisms that respond to DNA or RNA, the
novel mechanism used here responds to proteins, which are more commonly found
on cell surfaces and are largely responsible for transmembrane signaling in
cells. Finally, this is the first DNA-origami-based system that uses antibody
fragments to convey molecular messages—a feature that offers a controlled and
programmable way to replicate an immune response or develop new types of targeted
therapies.
“This work represents a major breakthrough in the
field of nanobiotechnology as it demonstrates the ability to leverage recent
advances in the field of DNA origami pioneered by researchers around the world,
including the Wyss Institute’s own William Shih, to meet a real-world
challenge, namely killing cancer cells with high specificity,” said Wyss
Institute Founding Director, Donald Ingber, MD, PhD. “This focus on
translating technologies from the laboratory into transformative products and
therapies is what the Wyss Institute is all about.”