Abstract An implantable system capable of long-term sustained release of antiretroviral drugs is needed to overcome patient adherence issues and achieve desired clinical outcomes in pre-exposure prophylaxis (PrEP) of HIV infection. The goal of this proposal, leveraging the extensive experience from a team of accomplished investigators with multidisciplinary backgrounds and based on encouraging preliminary findings, is to develop a novel, nanotechnology-based, implantable drug delivery device, the nanochannel drug delivery system (nDS), for sustained and constant release of antiretroviral drugs. The safety and efficacy of this implant, used for the delivery of tenofovir alafenamide fumarate and emtricitabine (TAF/FTC), will be validated in vitro and in established animal models. This broad objective will be achieved through the following specific aims: Aim 1) to develop nDS implants capable of sustained and constant release of TAF/FTC in rats and NHP for 60 days. Two nDS implants designed for small and large animal models, and incorporating a remotely controlled deactivation mechanism, will be developed and tested with TAF/FTC to establish release rates in vitro. In vivo analysis to evaluate safety of implant, test the deactivation mechanism, and determine the pharmacokinetics of nDS-delivered TAF/FTC will be conducted in healthy rat models. Aim 2) to assess the pharmacokinetics of constant delivery of TAF/FTC from nDS implants at target release rates for 60 days in non-human primates (NHP). Aim 3) to evaluate prevention of simian-human immunodeficiency virus (SHIV) infection by release of TAF/FTC from nDS implants through rectal challenge in NHP. This will be followed by pharmacometric modeling for future clinical evaluation in humans. The proposed work focuses at developing a novel implantable drug delivery device for the sustained delivery of antiretroviral drugs and the preclinical validation of the drug-device combination for pre-exposure prophylaxis of HIV infection. The nDS-TAF/FTC combination is expected to provide unique information about antiretroviral drugs’ efficacy in PrEP by eliminating issues related to patient compliance, gut absorption, and bioavailability from oral administration. The successful completion of this project will represent a significant step forward toward the clinical translation of the nDS implant for HIV PrEP and an effective preventive strategy for individuals who are at substantial risk of acquiring HIV infection.