DNA nanorobots deliver ‘suicide’ messages to cancer cells, other diseases

February 17, 2012

Hinged nanorobot opens when target molecules are sensed

Researchers at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed a nanorobotic 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.

Using the DNA origami method  (complex 3-D shapes and objects are constructed by folding strands of DNA), the researchers created a nanosize robot in the form of an open barrel whose two halves are connected by a hinge.

Recognition molecules

The nanorobot’s DNA barrel acts as a container that can hold various types of contents, including specific molecules with encoded instructions that can interact with specific signaling receptors on cell surfaces, including disease markers.

The barrel is normally held shut by special DNA latches. But when the latches find their targets, they reconfigure, causing the two halves of the barrel to swing open and expose its contents, or payload.


Schematic front orthographic view of DNA barrel of closed nanorobot loaded with a protein payload. Two DNA-aptamer locks fasten the front of the device on the left (boxed) and right.

Programming cancer-cell suicide

The researchers used this system to deliver instructions, encoded in antibody fragments, to two different types of cancer cells — leukemia and lymphoma.

In each case, the message to the cell was: activate your apoptosis or “suicide switch” — which allows aging or abnormal cells to be eliminated.

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 direct them to self-destruct. This programmable power means the system has the potential to one day be used to treat a variety of diseases.

Integrating sensing and logical computing functions

“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, a Wyss core faculty member and professor of genetics at Harvard Medical School, who is principal investigator on the project.


Aptamer lock mechanism, consisting of a DNA aptamer (blue) and a partially complementary strand (orange).

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.

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 re-close 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.

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.


Payloads such as gold nanoparticles (gold) and antibody fragments (magenta) can be loaded inside the nanorobot

Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Children’s Hospital Boston, and professor of bioengineering at Harvard’s School of Engineering and Applied Sciences. “This focus on translating technologies from the laboratory into transformative products and therapies is what the Wyss Institute is all about.”

Ref.: Shawn M. Douglas, Ido Bachelet, George M. Church, A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads, Science, 2012 [DOI: 10.1126/science.1214081]

Credit for images: Shawn M. Douglas et al./Science

Abstract of A Logic-Gated Nanorobot for Targeted Transport of Molecular Payloads

We describe an autonomous DNA nanorobot capable of transporting molecular payloads to cells, sensing cell surface inputs for conditional, triggered activation, and reconfiguring its structure for payload delivery. The device can be loaded with a variety of materials in a highly organized fashion and is controlled by an aptamer-encoded logic gate, enabling it to respond to a wide array of cues. We implemented several different logical AND gates and demonstrate their efficacy in selective regulation of nanorobot function. As a proof of principle, nanorobots loaded with combinations of antibody fragments were used in two different types of cell-signaling stimulation in tissue culture. Our prototype could inspire new designs with different selectivities and biologically active payloads for cell-targeting tasks.