Field-effect transistor (FET) biosensors have emerged as powerful tools for detecting biomolecules such as proteins, DNA, and viruses with high sensitivity and specificity. These devices leverage the electrical properties of semiconductors to transduce biological binding events into measurable signals, enabling label-free and real-time detection. The core principle involves functionalizing the FET gate with biorecognition elements that selectively interact with target analytes, modulating the channel conductance. Recent advancements in nanomaterials and device engineering have further enhanced their performance, making them suitable for applications in sepsis monitoring, cancer diagnostics, and infectious disease detection.

The foundation of FET biosensors lies in the functionalization of the gate dielectric or semiconductor surface with bioreceptors such as antibodies, aptamers, or DNA probes. For protein detection, antibodies are often immobilized on the gate using chemical linkers like silanes or thiols. DNA sensing relies on complementary oligonucleotide probes, while virus detection may use viral surface protein-specific ligands. The choice of functionalization chemistry is critical to maintaining bioreceptor activity and minimizing nonspecific binding. For instance, covalent immobilization via carbodiimide chemistry ensures stable attachment of antibodies, whereas electrostatic adsorption may be employed for DNA probes. Proper surface passivation with blocking agents like bovine serum albumin reduces background noise.

Label-free detection is a key advantage of FET biosensors, eliminating the need for fluorescent or enzymatic tags. When target molecules bind to the functionalized gate, they induce changes in surface charge or potential, altering the electric field within the semiconductor channel. This modulates the drain current, providing a direct electrical readout. For example, the binding of negatively charged DNA to a p-type FET increases hole accumulation, leading to a measurable current shift. Similarly, protein binding may screen gate charges or introduce dipole moments, further influencing the threshold voltage. The absence of labeling steps simplifies assay workflows and reduces costs, making FET biosensors attractive for point-of-care applications.

Nanomaterials have significantly improved FET biosensor performance by enhancing surface-to-volume ratios and charge sensitivity. Molybdenum disulfide (MoS2), a two-dimensional transition metal dichalcogenide, exhibits high carrier mobility and low electronic noise, enabling ultrasensitive detection. MoS2 FETs functionalized with aptamers have achieved detection limits in the femtomolar range for cancer biomarkers like prostate-specific antigen. Silicon nanowires (SiNWs) offer similar advantages, with their one-dimensional structure providing exceptional electrostatic control over the channel. SiNW FETs have demonstrated attomolar sensitivity for viral RNA detection by leveraging the Debye length effect in low-ionic-strength buffers. Graphene-based FETs are also notable for their ambipolar transport and biocompatibility, though challenges remain in achieving uniform functionalization across its inert surface.

In sepsis diagnostics, FET biosensors enable rapid detection of protein biomarkers like procalcitonin and C-reactive protein, which are critical for early intervention. Sepsis biomarkers typically appear in blood at nanomolar concentrations, necessitating high sensitivity. Functionalized SiNW FETs have been shown to detect procalcitonin at concentrations as low as 1 pg/mL in clinical samples, outperforming conventional ELISA methods. The real-time monitoring capability of FETs is particularly valuable for tracking dynamic biomarker levels during treatment. Similarly, in cancer diagnostics, FET biosensors have been employed to detect circulating tumor DNA (ctDNA) and exosomal proteins associated with malignancies. For instance, MoS2 FETs functionalized with anti-EpCAM antibodies can identify tumor-derived exosomes at concentrations relevant for early-stage cancer detection.

Despite their promise, FET biosensors face challenges related to drift and signal amplification. Drift, caused by unstable gate potentials or environmental fluctuations, can obscure binding signals over time. Techniques such as differential measurements using reference FETs or pulsed gate biasing have been employed to mitigate drift effects. Signal amplification strategies are often necessary to detect low-abundance targets. One approach involves enzymatic amplification, where horseradish peroxidase conjugated to detection antibodies generates localized charge changes upon substrate addition. Another method leverages nanoparticle labels that induce significant charge perturbations upon binding. For example, gold nanoparticles functionalized with secondary antibodies can enhance signals by orders of magnitude due to their high charge density.

Recent developments have pushed the limits of FET biosensor sensitivity through innovative device architectures and materials. Dual-gate FETs, which decouple sensing and transduction regions, have achieved zeptomolar detection limits by optimizing electrostatic control. Nanogap FETs, featuring sub-10-nm gaps between source and drain electrodes, exploit tunneling currents for single-molecule detection. Additionally, plasmonic FETs integrate metallic nanostructures to enhance local electric fields, improving signal-to-noise ratios. These advancements have enabled the detection of ultralow concentrations of viral particles, such as SARS-CoV-2 spike proteins, at clinically relevant levels without amplification steps.

The integration of FET biosensors into multiplexed platforms is another area of progress. By patterning multiple FETs with different bioreceptors on a single chip, simultaneous detection of multiple analytes becomes feasible. This is particularly useful for panels of sepsis biomarkers or cancer-specific mutations. Microfluidic integration further enhances reproducibility by standardizing sample delivery and reducing fouling. Some systems now incorporate machine learning algorithms to analyze complex signal patterns, improving diagnostic accuracy in heterogeneous samples like blood or saliva.

Looking ahead, the scalability and manufacturability of FET biosensors remain critical for widespread adoption. Solution-processable nanomaterials and printing techniques offer pathways to low-cost, disposable sensors. However, consistent functionalization and device-to-device uniformity must be addressed. Regulatory considerations for clinical use also necessitate rigorous validation against gold-standard methods. As these challenges are overcome, FET biosensors are poised to transform diagnostics by providing rapid, sensitive, and cost-effective solutions for detecting proteins, DNA, and viruses across healthcare settings.