Abstract Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to therapeutic regimen for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use and retrievability are desirable criteria for successful widespread clinical PrEP implementation. To date, LA PrEP strategies do not sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra- long acting islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years uninterrupted for durable and safe HIV prevention independent of user adherence. To achieve this goal, we propose the NanoDDI, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained and constant ISL release. The NanoDDI comprises a newly patented nanofluidic membrane, and ports for rapid, minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any complex pumps or equipment to extend implant use duration beyond 2 years. The nanofluidic membrane use nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, NanoDDI avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions, regardless of interindividual heterogeneity. Importantly, the NanoDDI addresses user preferences for discretion and longer dose duration. Here we will test the hypothesis that constant and sustained ISL delivery from NanoDDI will achieve preventative drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This proposal outlines a comprehensive preclinical framework fundamental for developing NanoDDI as a HIV PrEP platform, leveraging the team’s experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug formulation, and antiretroviral pharmacology. We aim 1) to develop and optimize NanoDDI and ISL formulation for sustained and constant release; 2) to assess pharmacokinetics (PK), tolerability, and safety of NanoDDI-ISL for 2 years in NHP and evaluate effectiveness of transcutaneous drug refilling; and 3) to comprehensively evaluate PrEP efficacy of NanoDDI-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile, vaginal and intravenous. Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery implants and will receive Merck’s scientific and technical support and drug supply for this study. We will use a milestone-driven research approach to advance the NanoDDI-ISL technology towards the ultimate goal of clinical translation.