There is a need for a paradigm shift in the treatment of drug-resistant epilepsy. Several routes have been explored to modulate or silence dysfunctional neural circuits, through genetic, electrical, magnetic or optical means. All have serious limitations due to the unphysiological mechanisms used to regulate neuronal activity. In IN-FET, we address this issue by manipulating the elementary building blocks of cell excitability: ions. IN-FET tackles the visionary idea of altering neuronal firing and synaptic transmission by direct ionic actuation at the microscopic scale, while monitoring cell responses by arrays of nanoscale transistors. We will develop and test, in vitro, the use of active polymers to trap or release electrochemically specific ions in the extracellular milieu surrounding neurons. These will be integrated with ion sensors and ultra-sensitive nanowire arrays, offering closed-loop regulation of cellular electrical activity. We will deliver for the first time a device that can physiologically modulate the neuronal membrane potential, the synaptic release probability, and glutamatergic NMDA receptors activation by altering potassium, calcium, and magnesium ionic concentrations in a controlled and spatially-confined manner. High-resolution simultaneous probing of cell activity will be performed by Si-nanowire vertical transistors, penetrating the membranes and detecting the cell electrical activity at unprecedented spatial and temporal resolutions. In conclusion, IN-FET's multidisciplinary consortium brings together state-of-the-art electrochemistry, 3-d nanofabrication, nanoelectronics, and numerical simulations, and combines neuronal biophysics to device modeling. IN-FET will thus establish the proof-of-principle for a breakthrough biocompatible neuromodulation technology, with a clear impact for future brain implants for epilepsy treatment, advancing neuroscience, biomedical microsystems engineering, and nano-neurotechnology.