Globally, over 50% of those infected with HIV are women, and annually, ~50% of all pregnancies are unplanned. Therefore, there is a critical need to promote female-controlled methods of multipurpose prevention technologies (MPTs) and delivery strategies that can be disassociated from the sex act. Long-acting (LA) formulations that provide sustained drug release over weeks offer several advantages, including relief from “pill fatigue” and better protection of health privacy. As such, LA delivery systems hold great potential to enhance compliance to HIV pre-exposure prophylaxis (PrEP) and help curb the global HIV epidemic. Amongst LA formulations currently in development or recently approved, injectable formulations provide several advantages over implantable devices that require an applicator (e.g. Trocar) or that are sex specific (e.g. vaginal rings, inserts). Injectable formulations are well tolerated by men and women, are efficacious for contraception, and have high patient acceptability and compliance1-4. Apretude, a LA injectable nanoparticle suspensions of cabotegravir (CAB), is the first FDA-approved for HIV PrEP5-7. Although effective, Apretude requires six (6) intramuscular (IM) injections per year after 2 once-monthly starter injections. Lenacapavir (LEN) is another LA injectable currently in Phase 3 clinical trials as a once-every-six-months subcutaneous injection for HIV PrEP8. Despite these advances in HIV PrEP, currently there are no LA injectable MPT formulations in development mainly because of limitations of current LA injectable formulations utilizing nanoparticle suspensions whereby two drugs cannot be combined into a single injection. In this R61/R33 grant and building on our strong preliminary data and current development, we propose a comprehensive evaluation and translation of a first-in-line injectable MPT that offers durable and sustained protection from HIV transmission, high efficacy of contraception, increased user compliance, and the abi