Drug delivery to the Central Nervous System (CNS) is limited by complex biological barriers generally termed the blood–brain barriers (BBB). The nanotechnology-enabled innovation to be developed in INTREPIDUS will lay the foundations for a new route of administering drugs to the CNS. It is based on a radically new implantable device able to put in touch target molecules present in the Cerebrospinal Fluid (CSF) with drugs inside of the device (pseudodelivery). This is achieved by means of a smart architecture of selectively-permeable nanoporous membranes that allow the influx of small molecules (targets) at the time of preventing the efflux of therapeutics of larger molecular size (nanosieve). Acting directly on the CSF is expected to be highly effective while no immune responses are expected from biological drugs as they do not enter in contact with cells (immunoisolation). Thus, the ultimate aim is to change the paradigm of route of administration of drugs for a wide number of neurological conditions: from peripherally delivered to intrathecally pseudodelivered. Specifically in this project, we will develop and test an intrathecally implantable device to be used in combination with two therapeutics to clear β-amyloid (Aβ) from the CSF as a promising therapy for Alzheimer’s disease (AD). The project is composed of interconnected work packages aimed at refining the design of the device, manufacturing all components, and assembling the prototype. Proof-of-concept will be made in multiple levels: in vitro, ex vivo (human and mice CSF) and in vivo (transgenic AD mice). Strategies to optimize biocompatibility and biofouling of nanoporous membranes are an important additional objective.