The Virus Grabber

How do you attach a fluorescent marker to a single virus particle to create a rapid, 30-minute COVID-19 test matching the sensitivity of the gold-standard qPCR molecular tests? The answer: grab it with a tiny nanorobot hand.

That’s what a research team at the University of Illinois, USA, have achieved. Their DNA NanoGripper, introduced in a paper in Science Robotics, is a four-fingered nanorobotic hand formed from a single DNA strand. We caught up with lead author Xing Wang to find out more about the intriguing invention and its potential applications.

What inspired the development of the NanoGripper?
 

For a robot to perform functions such as recognition, capture, and transportation of an entity, grasping is an essential capability. Human hands and bird claws are naturally evolved “machines” that can grab different macroscopic objects. However, hand- and claw-like mechanisms have not yet been realized at a nanometer scale. That gap inspired and motivated my team to create the NanoGripper robot that can accommodate grasping of nanoscale objects of different sizes. 

How does its DNA-based structure differ from traditional approaches in nanotechnology?
 

In aqueous buffers and physiological fluids, DNA retains its double helical structure, with a 2-nm diameter and 3.4-nm distance per DNA turn. Furthermore, the sequence of DNA can be easily programmed. These features make DNA an ideal molecular building block for the construction of nanoscale objects with precisely defined dimensions and curvatures.

DNA nanostructures can serve as biocompatible and stable molecular pegboards in which to arrange external ligands, such as aptamers, peptides, proteins, and nanoparticles (NPs). These can be arranged in both 2D and 3D spaces into any patterns with desired spacing and valency at the nanometer scale, offering key advantages over other nanomaterials.

With excellent programmable mechanical properties, DNA is a versatile material for building nanorobots for various applications. What’s more, DNA can now be affordably synthesized on a large scale via a variety of chemical and enzymatical approaches.

Could you describe the key features of the NanoGripper's design and how these features enable it to interact specifically with viruses like SARS-CoV-2?
 

The Nanogripper design is based around four fingers and a palm, comprising 13 segments and 12 joints. All the components are folded from a single DNA origami piece, the design for which was produced by creatively adapting a macroscopic machine design procedure. The angle and degree of bending of the four fingers are designed to ensure effective grasping of nanoscale objects of different sizes. 

The single DNA piece design also confers structural advantages. On a mechanical front, the design gives the NanoGripper the stability to maintain its structural integrity. Synthetically, it enables a one-pot/one-step reaction that greatly simplifies the production workflow and thus, facilitates large scale production of the nanobot at relatively low cost. Both advantages will benefit the utility of the NanoGripper in biomedical applications, including disease detection and treatment, as demonstrated in the current work.

Binding between the NanoGripper and virus particle is enabled by the virus spike-targeting aptamers placed on the fingers’ surfaces. These aptamers are arranged into a spatial pattern that specifically matches that of the trimeric spike protein on the virus outer surface. Such pattern-recognition-enabled multivalent interaction – a principle developed by my group – has induced ultrahigh NanoGripper–virus binding avidity, resulting in enhanced virus diagnosis sensitivity. 

Additionally, the pliability of the fingers can promote and maximize such multivalent interactions. Compared to rigid 2D plate-shaped nanostructures, the Nanogripper’s fingers can accommodate different poses to wrap around virions of different sizes more effectively.

How does the NanoGripper's virus detection capabilities compare to existing diagnostic methods, such as qPCR, in terms of sensitivity, accuracy, and scalability?
 

By directly detecting the intact virus particles, the NanoGripper enabled virus diagnosis approach is rapid – within 30 mins. It circumvents the need for PCR tests, which can cause a great loss of viral RNA materials, takes more time to finish, and needs sophisticated instruments.

By avoiding the loss of virus materials and providing high binding avidity/selectivity, the NanoGripper-based approach can offer sensitivity and accuracy equivalent to RT-qPCR. The reagents and supplies are easier to acquire, and the cost of each NanoGripper-based test is around $1.08 – much lower than the cost of a qPCR or ELISA test. Thus, the NanoGripper approach provides more attractive availability and scalability.

The NanoGripper has been demonstrated for COVID-19 detection. What challenges and opportunities do you foresee in adapting this technology to detect other pathogens?
 

The NanoGripper platform can be easily adapted to detect other pathogens like influenza, HIV, and HBV, after placing multiple specific virus-binding aptamers (or nanobodies) on the fingers’ surface with a matching spatial pattern. 

The team has already demonstrated the utilization of the NanoGripper in detecting infectious HBV particles, and will publish the results in due course.

How do you envision integrating the NanoGripper with existing diagnostic platforms in laboratory medicine to enhance workflows and patient care?
 

The NanoGripper can be integrated with a lateral flow assay (LFA) paper strip platform for the development of rapid, sensitive, and inexpensive at-home or point-of care virus detection. 

Whilst the sensitivity of an LFA may be a bit lower than that demonstrated in the current paper – using photonic crystal enhanced signal for digital counting – the approach would simplify the NanoGripper-enabled diagnosis workflow. Further, it would offer point-of-use virus testing in less than 15 minutes, greatly enhancing the patient care experience.

What advancements in nanorobotics and biomolecular engineering do you believe will be crucial for realizing the full potential of the NanoGripper in personalized medicine?
 

To my knowledge, obtaining molecular binders (aptamers, nanobodies, etc.) that can specifically bind the biomarkers of emerging biological threats (e.g., pathogens and cancers) is one of the “rate-limiting” steps for realizing the full potential of the NanoGripper or other DNA nanostructure platforms in medicine. To address the challenge, we (and others) are developing in silico-based aptamer and nanobody selection and engineering methods, hoping to rapidly obtain useful molecular binders that can be placed on the NanoGripper to combat emerging biological threats.