Light-Based Sensor Detects Cancer Biomarkers at Ultra-Low Concentrations in Blood

Researchers have developed a highly sensitive light-based sensor that can detect extremely low concentrations of cancer biomarkers in the blood. In a study published in the journal Optica, the sensors were capable of spotting a lung cancer biomarker in blood samples even when only a few molecules are present, showing promise for early cancer detection when biomarker levels are too low to be found using conventional methods.

The sensor detected lung cancer biomarkers from patient samples at sub-attomolar levels, producing a clear signal even when only a few molecules were present in a sample. Biomarkers such as proteins, DNA or other molecules can be used to reveal the presence, progression or risk of cancer and other diseases. However, one of the main challenges in early disease diagnosis is the extremely low concentration of biomarkers present at the onset.

"Our sensor combines nanostructures made of DNA with quantum dots and CRISPR gene editing technology to detect faint biomarker signals using a light-based approach known as second harmonic generation (SHG)," said the research team leader from Shenzhen University in China. "If successful, this approach could help make disease treatments simpler, potentially improve survival rates and lower overall healthcare costs."

The sensors are made of a flat layer of molybdenum disulfide, a semiconducting material with ideal properties to support SHG—an optical phenomenon that reduces by half the wavelength of incoming light. The new sensor is based on SHG, a nonlinear optical process in which incoming light is converted to light at half the wavelength.

Using DNA nanostructures shaped like pyramids, the scientists tethered quantum dots at precise locations on the sensor's surface, enhancing the strength of the SHG signal produced. The researchers used DNA tetrahedrons—self-assembled, pyramid-like nanostructures made entirely from DNA—to tether tiny quantum dots at precise distances from the MoS₂ surface. The quantum dots enhance the local optical field, strengthening the SHG signal.

With CRISPR, the sensor can be programmed to recognize any desired target. They applied CRISPR-Cas gene editing to detect specific biomarkers. When the Cas12a protein used for CRISPR recognizes a target biomarker, it cuts the DNA holding the quantum dots in place, which causes a measurable drop in SHG signal. Because the SHG signal has minimal background noise, even very low concentrations of biomarkers can be detected.

"Instead of viewing DNA only as a biological substance, we use it as programmable building blocks, allowing us to assemble the components of our sensor with nanometer-level precision," said the team leader. "By combining optical nonlinear sensing, which effectively minimizes background noise, with an amplification-free design, our method offers a distinct balance of speed and precision."

Unlike conventional detection methods that require the amplification of the DNA or RNA target in order to get a strong enough signal, these quantum sensors can directly detect their target even at ultra-low concentrations. Detecting biomarkers usually requires amplifying tiny amounts of molecules, a process that can be time-consuming and costly. This technology could therefore make workflows much faster and affordable while preventing potential errors introduced by complex amplification workflows.

The researchers tested their sensor design by programming it to detect miR-21, a microRNA biomarker linked to lung cancer growth and metastasis. After verifying that it could detect this marker in a simple buffer solution, they also showed that it could detect the biomarker in human serum from lung cancer patients, simulating a real blood test.

"The sensor worked exceptionally well, showing that integrating optics, nanomaterials and biology can be an effective strategy to optimize a device," said the team leader. "The sensor was also highly specific—ignoring other similar RNA strands and detecting only the lung cancer target."

The sensing technique was designed to be programmable, which could allow it to detect viruses, bacteria or environmental toxins as well as various biomarkers such as those associated with Alzheimer's disease.

"For early diagnosis, this method holds promise for enabling simple blood screenings for lung cancer before a tumor might be visible on a CT scan," said the team leader. "It could also help advance personalized treatment options by allowing doctors to monitor a patient's biomarker levels daily or weekly to assess drug efficacy, rather than waiting months for imaging results."

Going forward, the team plans to continue improving the sensor design and making it smaller, with the ultimate goal of developing a portable device that can be easily used both in clinical settings and remote locations to support early cancer detection. The researchers plan to focus on miniaturizing the optical setup. Their goal is to turn it into a portable device that could be used at the bedside, in clinics or even in low-resource remote locations.