Georgia Tech researchers have developed biosensors with advanced sleuthing skills and the technology may revolutionize cancer detection and monitoring. 

The tiny detectives can identify key biological markers using logical reasoning inspired by the “AND” function in computers — like, when you need your username and password to log in. And unlike traditional biosensors comprised of genetic materials — cells, bits of DNA — these are made of manufactured molecules.

These new biosensors are more precise and simpler to manufacture, reducing the number of false positives and making them more practical for clinical use. And because the sensors are cell-free, there’s a reduced risk for immunogenic side effects.

“We think the accuracy and simplicity of our biosensors will lead to accessible, personalized, and effective treatments, ultimately saving lives,” said Gabe Kwong, associate professor and Robert A. Milton Endowed Chair in the Wallace H. Coulter Department of Biomedical Engineering, who led the study, published this month in Nature Nanotechnology. 

Breaking With Tradition

The researchers set out to address the limitations in current biosensors for cancer, like the ones designed for CAR-T cells to allow them to recognize tumor cells. These advanced biosensors are made of genetic material, and there is growing interest to reduce the potential for off-target toxicity by using Boolean “AND-gate” computer logic. That means they’re designed to release a signal only when two specific conditions are met.

“Traditionally, these biosensors involve genetic engineering using cell-based systems, which is a complex, time-consuming, and expensive process,” said Kwong.

So, his team developed biosensors made of iron oxide nanoparticles and special molecules called cyclic peptides. Synthesizing nanomaterials and peptides is a simpler, less costly process than genetic engineering, according to Kwong, “which means we can likely achieve large-scale, economical production of high-precision biosensors.”

Unlocking the AND-gate

Biosensors detect cancer signals and track treatment progress by turning biological signals into readable outputs for doctors. With AND-gate logic, two distinct inputs are required for an output. 

Accordingly, the researchers engineered cyclic peptides — small amino acid chains — to respond only when they encounter two specific types of enzymes, proteases called granzyme B (secreted by the immune system) and matrix metalloproteinase (from cancer cells). The peptides generate a signal when both proteases are present and active.

Think of a high-security lock that needs two unique keys to open. In this scenario, the peptides are the lock, activating the sensor signal only when cancer is present and being confronted by the immune system. 

“Our peptides allow for greater accuracy in detecting cancer activity,” said the study’s lead author, Anirudh Sivakumar, a postdoctoral researcher in Kwong’s Laboratory for Synthetic Immunity. “It’s very specific, which is important for knowing when immune cells are targeting and killing tumor cells.”

Super Specific

In animal studies, the biosensors successfully distinguished between tumors that responded to a common cancer treatment called immune checkpoint blockade therapy — ICBT, which enhances the immune system — from tumors that resisted treatment. 

During these tests, the sensors also demonstrated their ability to avoid false signals from other, unrelated health issues, such as when the immune system confronted a flu infection in the lungs, away from the tumor.

“This level of specificity can be game changing,” Kwong said. “Imagine being able to identify which patients are responding to the therapy early in their treatment. That would save time and improve patient outcomes.”

The first step toward this simpler, precise form of cancer diagnostics began with an ambitious but humble ($50,000) seed grant from the Petit Institute for Bioengineering and Bioscience five years ago for a collaboration between Kwong’s lab and the lab of M.G. Finn, professor and chair in the School of Chemistry and Biochemistry.

It evolved into a multi-institutional project supported by grants from the National Science Foundation and National Institutes of Health that included researchers from the University of California-Riverside, as well as Georgia Tech faculty researchers Finn and Peng Qiu, associate professor in the Coulter Department.

“The progression of the research, from an initial seed grant all the way to animal studies, was very smooth,” Kwong said. “Ultimately, a collaborative, multidisciplinary effort turned our early vision into something that could have a great impact in healthcare.”

Citation: Anirudh Sivakumar, Hathaichanok Phuengkham, Hitha Rajesh, Quoc D. Mac, Leonard C. Rogers, Aaron D. Silva Trenkle, Swapnil Subhash Bawage, Robert Hincapie, Zhonghan Li, Sofia Vainikos, Inho Lee, Min Xue, Peng Qiu, M. G. Finn, Gabriel A. Kwong. “AND-gated protease-activated nanosensors for programmable detection of anti-tumour immunity.” Nature Nanotechnology (January 2025).  https://doi.org/10.1038/s41565-024-01834-8

Funding: This research was supported in part by National Institutes of Health (NIH) grants 5U01CA265711, 5R01CA237210, 1DP2HD091793, and 5DP1CA280832.

Samer Mabrouk and Omer Inan have been working on a wearable, battery-powered device that monitors joint health and gives personalized strengthening exercises. Inan and Mabrouk’s new company, Arthroba, created a device of the same name that uses electrical sensors to track swelling and tissue damage in the knee, ankle, and other critical joints.

Ebenezer Fanijo and David Citrin lead the “Waste Materials Processing” research initiative for the Institute for Matter and Systems at Georgia Tech. Their research in this role focuses on creating innovative construction materials from waste streams to reduce carbon emissions in construction. Fanijo is a professor in the School of Building Construction and Citrin is a professor in the School of Electrical and Computer Engineering.

In this brief Q&A, Fanijo and Citrin discuss their research focus, how it relates to Matter and System’s core research focuses, and the national impact of this initiative.

What is your field of expertise and at what point in your life did you first become interested in this area?
Fanijo - My research focuses on sustainable buildings and civil infrastructure, particularly decarbonizing through low-carbon materials and alternative energy sources. I also specialize in in-situ nanoscale quantification of cementitious materials and metals using advanced characterization techniques. My interest in this field grew during my graduate studies and after attending the First International Conference on Sustainable Production and Use of Cement and Concrete.
Citrin - Several years ago, I supervised a masters project using an automated imaging system to identify construction materials. My core interests are in terahertz imaging and applications of machine learning, so the IMS project brought these two together.

What questions or challenges sparked your current research? 
Fanijo - Buildings account for 39% of global energy-related CO2 emissions and 35% of energy consumption, primarily due to manufacturing, materials, and transportation. Therefore, advanced research into innovative construction materials derived from waste streams is essential to reduce carbon emissions throughout the building lifecycle.

Citrin - The societal problems of how to reuse construction waste is urgent. Identifying those materials that can be reused and separating them from those that are tainted presents fascinating technical problems and is a tremendous challenge.

Matter and systems refer to the transformational technological and societal systems that arise from the convergence of innovative materials, devices, and processes. Why is your initiative important to the development of the IMS research strategy? 
While “construction materials” evokes low tech, in fact, there have been tremendous advances in the materials as well as how they are used.  Connecting such advances with the environmental challenges we face with new technological opportunities to mitigate these problems fits squarely in the remit of the IMS research strategy.

What are the broader global and social benefits of the research you and your team conduct? 
One of the greatest components by volume filling landfills is construction waste.  This waste is typically unsorted by material and tainting by hazardous waste is also common, making recycling prohibitively difficult. By sorting the materials in real time and identifying tainted versus untainted waste, we aim to reduce the quantity of such waste landfilled and to reduce the quantities of new materials made by reusing the old.

What are your plans for engaging a wider Georgia Tech faculty pool with the Institute for Matter and Systems research? 
The leads on this project are experts in construction waste and in terahertz imaging.  But what we envisage for this program will ultimately involve image processing and machine learning, materials science and chemical engineering, as well as actively recycling these materials for reuse.

Margaret E. Kosal leads the "Investigating the Future of Metamaterials for National Security and To Avoid Technological Surprise" research initiative for the Institute for Matter and Systems at Georgia Tech. In this role, her research focuses on investigating technical aspects of cutting-edge metamaterials design, synthesis, and development to understand the potential impacts of this type of emerging technology on national security and geopolitics. Kosal is also a professor in the Sam Nunn School of International Affairs.

In this brief Q&A, Kosal discusses her research focus, how it relates to Matter and System’s core research focuses, and the national impact of this initiative.

What is your field of expertise and at what point in your life did you first become interested in this area?
My formal education and background are in the physical sciences (PhD Chemistry); my scholarship, research, teaching, external engagement, and impact are intrinsically interdisciplinary; and I have found a scholarly home and community in the international relations discipline, primarily working in the areas of security and science and technology (S&T) policy.

What questions or challenges sparked your current research? 
With one of my PhD students, I’d previously done research on potential disruptive potential of metamaterials, finding them to potentially be a potentially revolutionary innovation to the power of global and regional hegemons. That work found that revisionist actors, primarily non-state actors, likely will benefit disproportionately from acquiring a metamaterial adaptive camouflage (MMAC) capability but will struggle to do so due to the technical challenge of advanced R&D, particularly in the near and mid-term. The implication found was that status quo powers – who are likely to be the first to develop a viable capability – must emphasize parallel development of countermeasures and limit the negative potential of the technology’s proliferation. With this project, I want to dive deeper into the technical aspects of cutting-edge metamaterials design, synthesis, and development to understand the potential impacts of this type of emerging technology on national security and geopolitics.

Matter and systems refer to the transformational technological and societal systems that arise from the convergence of innovative materials, devices, and processes. Why is your initiative important to the development of the IMS research strategy? 
In November 2016, US Army Lieutenant General HR McMaster, then-Deputy Commanding General for Army Futures and Director of the Army Capability Integration Center (ARCIC) invoked the concept of invisible tanks at meeting on Ground Combat Platforms at the Institute of Land Warfare. I was speaking at the same meeting and commented in my remarks on the need for new capabilities that shift the approach to survivability from protection via mass (which is limiting) to capabilities for active defense and adaptive responses such as via meta-materials. 

Over the last century, the dominant mechanism to achieve parity or asymmetric advantages in land warfare (e.g., maneuver warfare using tanks and other vehicles) has relied on armor and other materials that more effectively absorb kinetic impacts. In the mid-20th Century, the US Air Force shifted to relying on speed and stealth for asymmetric advantage. New conceptual approaches are needed and will have significant implications for conflict, cooperation, and the nature of land warfare. In the case of land warfare (as with air power), materials and systems are fundamental to being able to achieve those asymmetric advantages. The convergence of these innovative materials into existing and new capabilities (vehicles) is likely to result in revolutionary changes to societal systems.

What are the broader global and social benefits of the research you and your team conduct? 
My scholarship significantly contributes to a better and more nuanced understanding of the relationships among science, technology, and security, emphasizing the complex interactions among science, technology, geopolitics, knowledge, innovation, governance (laws and treaties), diplomacy, and institutions. My work explains how these phenomena intersect and impact geopolitics by developing and testing novel analytical frameworks.

What are your plans for engaging a wider Georgia Tech faculty pool with the Institute for Matter and Systems research? 
I’m going to be reaching out directly to GT faculty and GTRI researchers in Engineering and the Sciences. I am also interested in exploring how my research integrates and might further other IMS Research Initiatives (e.g. “Mechanical Metamaterials” (Rocklin/PHYS) and Research Centers (e.g., the Center for Organic Photonics and Electronics).

The Institute for Matter and Systems (IMS) at Georgia Tech has announced the fall 2024 core facility seed grant recipients. The primary purpose of this program is to give graduate students in diverse disciplines working on original and unfunded research in micro- and nanoscale projects the opportunity to access the most advanced academic cleanroom space in the Southeast. In addition to accessing the labs' high-level fabrication, lithography, and characterization tools, the awardees will have the opportunity to gain proficiency in cleanroom and tool methodology and access the consultation services provided by research staff members in IMS. Seed Grant awardees are also provided travel support to present their research at a scientific conference.

In addition to student research skill development, this biannual grant program gives faculty with novel research topics the ability to develop preliminary data to pursue follow-up funding sources. The Core Facility Seed Grant program is supported in part by the Southeastern Nanotechnology Infrastructure Corridor (SENIC), a member of the National Science Foundation’s National Nanotechnology Coordinated Infrastructure (NNCI).

The five winning projects in this round were awarded IMS cleanroom and lab access time to be used over the next year. 

The Fall 2024 IMS Core Facility Seed Grant recipients are:

Manufacturing of a Diamagnetically Enhanced PEM Electrolysis Cell
PI: Alvaro Romero-Calvo
Student: Shay Vitale
Daniel Guggenheim School of Aerospace Engineering

Biomimicking Organ-On-a-Chip Models
PI: Nick Housley
Student: Aref Valipour
School of Biological Sciences                                                            

Single-shot LWIR Hyperspectral Imaging Using Meta-optics
PI: Shu Jia
Student: Jooyeong Yun (School of Electrical and Computer Engineering)
The Wallace H. Coulter Department of Biomedical Engineering

Large-area Three-dimensional Nanolithography Using Two-photon Polymerization
PI: Sourabh Saha
Student: Golnaz Aminaltojjari
George W. Woodruff School of Mechanical Engineering

Effects of Geochemical Constraints on the Redistribution of Rare Earth Elements (REE) during Chemical Weathering
PI: Yuanzhi Tang
Student: Hang Xu
School of Earth and Atmospheric Sciences