Abstract: The present disclosure provides devices, systems, and methods capable of optimizing in vivo electrochemical measurement of a molecule of interest, for example glucose. Disclosed aspects may include an interference zapping layer, to which an electric potential may be applied to prevent or minimize various interfering molecules from reaching a working electrode. Aspects of the present disclosure may additionally or alternatively include a sensor including multiple working electrodes. The sensors having multiple working electrodes may measure background current during sensing in order to determine background current specific to each electrode, current due to electrochemical interferents, and current due to the molecule of interest. Sensors may also be capable of executing a measurement mode whereby a plurality of currents are measured over a range of interference zapping layer potentials and a range of working electrode potentials.