Dual-gate ion-sensitive field effect transistors (ISFETs) for disease diagnostics are disclosed herein. An exemplary dual-gate ISFET includes a gate structure and a fluidic gate structure disposed over opposite surfaces of a device substrate. The gate structure is disposed over a channel region defined between a source region and a drain region in the device substrate. The fluidic gate structure includes a sensing well that is disposed over the channel region. The sensing well includes a sensing layer and an electrolyte solution. The electrolyte solution includes a constituent that can react with a product of an enzymatic reaction that occurs when an enzyme-modified detection mechanism detects an analyte. The sensing layer can react with a first ion generated from the enzymatic reaction and a second ion generated from a reaction between the product of the enzymatic reaction and the constituent, such that the dual-gate ISFET generates an enhanced electrical signal.