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 comprising 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, personalised, and effective treatments, ultimately saving lives,” says Gabe Kwong, Associate Professor at Georgia Tech, who led the study.
Solving problems with current sensors
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 recognise tumour cells.
These advanced biosensors are made of genetic material, and there is growing interest in reducing 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,” says Kwong.
So, his team developed biosensors made of iron oxide nanoparticles and special molecules called cyclic peptides.
Synthesising 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”.
Getting super specific
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,” says 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 tumour cells.”
In animal studies, the biosensors successfully distinguished between tumours that responded to a common cancer treatment called immune checkpoint blockade therapy – ICBT, which enhances the immune system – from tumours 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 tumour.
“This level of specificity can be game-changing,” Kwong says. “Imagine being able to identify which patients are responding to the therapy early in their treatment. That would save time and improve patient outcomes.”