Ultrasensitive and specific detection of low-abundance tumor biomarkers remains a major challenge for early and minimally invasive cancer diagnosis. Here, we present a high-performance biosensing platform that integrates a genetically engineered bacterial S-layer with an AlGaN/GaN high-electron-mobility transistor (HEMT) sensor for label-free detection of tumor antigens. As a proof-of-concept, the ovarian cancer antigen human epididymis protein 4 (HE4) was selected . Specifically, the S-layer protein rSbpA was fused with HE4-specific nanobody 1G8 to construct a bifunctional membrane capable of self-assembling into an ordered biorecognition layer on the sensor surface. Compared to conventional chemical crosslinking, S-layer-driven assembly increased antibody loading by 50 % and minimized nonspecific adsorption in plasma environments. The resulting HEMT sensor detected HE4 across a dynamic linear range (10⁻²¹ to 10⁻¹⁴ M), identifying patients with ovarian cancer with 100 % diagnostic accuracy (AUC = 1.0). This study establishes a versatile and modular biosensing strategy for ultra-low-abundance biomarker detection with broad potential applications in the precision diagnostics of cancer and other diseases.

The use of microRNAs as clinical cancer biomarkers is hindered by the absence of accurate, sensitive and rapid assays for their detection in biofluids. Here we report a biosensing approach, SpLig-HEMT, that combines an RNA splint-ligation reaction with an AlGaN/GaN high-electron-mobility transistor biosensor for ultrasensitive miRNA detection. In this system, HEMT functions as a highly effective voltage amplifier to enhance detection sensitivity, while the splint-ligation reaction ensures precise discrimination of single-nucleotide mutations. By detecting miRNA-21, the SpLig-HEMT biosensor achieves an exceptional limit of detection of 10⁻¹⁸ M within 30 min, with a dynamic range from 10⁻¹⁸ M to 10⁻¹³ M. No detectable response is observed for one-mismatch miR-21. Furthermore, the SpLig-HEMT biosensor enables direct analysis of blood serum samples, effectively distinguishing between healthy individuals and patients with ovarian cancer. This study addresses critical challenges in miRNA detection and presents a promising tool for cancer diagnosis and prognosis.

The COVID-19 pandemic has highlighted the need for rapid and sensitive detection of SARS-CoV-2. Here, we report an ultrasensitive SARS-CoV-2 immunosensor by integration of an AlGaN/GaN high-electron-mobility transistor (HEMT) and anti-SARS-CoV-2 spike protein antibody. The AlGaN/GaN HEMT immunosensor has demonstrated the capability to detect SARS-CoV-2 spike proteins at an impressively low concentration of 10−22 M. The sensor was also applied to pseudoviruses and SARS-CoV-2 ΔN virions that display the Spike proteins with a single virion particle sensitivity. These features validate the potential of AlGaN/GaN HEMT biosensors for point of care tests targeting SARS-CoV-2. This research not only provides the first HEMT biosensing platform for ultrasensitive and label-free detection of SARS-CoV-2.