An “ultra” long-acting (LA) integrase strand transfer inhibitor was created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led, to the best of our knowledge, a “first in class” 18-carbon chain modified prodrug nanocrystal (coined as NM2DTG). Ideal physiochemical and pharmacokinetic (PK) properties facilitated slow drug release from tissue macrophage prodrug depot stores for up to one year after a single intramuscular injection. Both the muscle injection site and secondary lymphoid tissues were depots of prodrug hydrolysis; dependent on nanocrystal dissolution and prodrug release rates, drug-depot volume, perfusion, and cell-tissue pH. Each affected an extended NM2DTG apparent half-life by recorded PK parameters. The NM2DTG LA product can impact therapeutic adherence, tolerability, and access to a widely used integrase inhibitor in resource-limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes.