A monolithic biosensing platform is presented for miniaturized amperometric electrochemical sensing in CMOS. The system consists of a fully integrated current readout circuit for differential current measurement as well as on-die sensors developed by growing platinum nanostructures (Pt-nanoS) on top of electrodes implemented with the top metal layer. The circuit is based on the switch–capacitor technique and includes pseudodifferential integrators for concurrent sampling of the differential sensor currents. The circuit further includes a differential to single converter and a programmable gain amplifier prior to an ADC. The system is fabricated in 0.35 μm technology and measures current within ±20 μA with minimum input-referred noise of 0.47 pA and consumes 9.3 mW from a 3.3 V supply. Differential sensing for nanostructured sensors is proposed to build highly sensitive and offset-free sensors for metabolite detection. This is successfully tested for bio-nano-sensors for the measurement of glucose in submilli molar concentrations with the proposed readout IC. The on-die electrodes are nanostructured and cyclic voltammetry run successfully through the readout IC to demonstrate detection of H2O2.