Electronic measurements of engineered nanostructures comprised solely of DNA (DNA nanostructures) enable new signal conditioning modalities in biosensing. Here, we demonstrate how these DNA nanostructures alter their conformation upon binding a nucleic acid analyte to drastically, and reversibly, amplify the measured electrochemical signal. This amplification was controlled by the applied electrical field to achieve a response ≈2×104times greater than that measured from DNA hybridization. Because the amplification is independent of the interaction between the analyte and the DNA nanostructure, our approach provides a platform for tuning the response of the system for high performance that is agnostic of the end application. These molecularly precise self-assembled DNA nanostructures when paired with scalable electronic readout can therefore lead the way to highly sensitive multiplexed biosensing.