Project Summary Electronic biosensors have been playing increasingly important roles in medical diagnostics. Early detections of various biomarkers are desired to provide timely diagnosis for the prevention and treatment of diseases. However, current electronic biosensors are limited in biodetection, often attributed to nonspecific interferences from a complicated ionic environment in bodily solutions. Specifically, charge screening has prevented field-effect biosensors from real-time biodetection in physiological environment. We intend to bring in and validate a new biosensor concept, which can be free of nonspecific charge interference and provide generic solution to the specific biodetection. We also intend to apply the biosensor in the early detection of tick- borne diseases, which have imposed serious threat to public health but lacked means in early detection for timely treatment. Inspired by the mechanotransduction in biological organelles, we will employ a `mechanogating' sensing mechanism that is orthogonal and hence resilient to charge interference. Specifically, we propose to design a biosensor based on a suspended nanotransistor exposed to analyte flow; the binding biomolecules are expected to increase the effective cross-sectional area of the nanotransistor and hence the drag force by the fluid flow; the induced strain will lead to a conductance change through the piezoresistance effect. To realize the goals, in Aim 1 we will assembly and integrate highly suspended nanotransistors as the biosensors specifically designed for the proposed sensing mechanism. In Aim 2, we will evaluate and verify the biosensor function and performance in high ionic strength mimicking the physiological environment. In Aim 3, we will implement the biosensor for the selective detection of pathogens of tick-borne diseases. If successful, the biosensor will provide a practical solution for improved/timely treatment in tick-borne diseases. The research is expected to create a new class of biosensors, which will transcend the inability of field-effect biosensors and realize generic biodetection in physiological environment, leading to advanced biomedical devices for versatile point-of-care diagnostics.