Natural killer (NK) cells are attractive effector cells of the innate immune system against human immunodeficiency virus (HIV) and cancer.However,NK cell therapies are limited by the fact that target cells evade NK cells,for example,in latent reservoirs (in HIV)or through upregulation of inhibitory signals (in cancer).To address this limitation,we describe a biodegradable nanoparticlebased priming approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells.We present poly(lactic-co-glycolic acid) (PLGA) nanodepots (NDs) that co-encapsulate prostratin,a latency-reversing agent,and anti-CD25 (aCD25),a cell surface binding antibody,to enhance primary NK cell function against HIV and cancer.We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs (termed Pro-aCD25-NDs).Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs.The NDs successfully released both active prostratin and anti-CD25,and with controllable release kinetics.When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells,the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25,and other controls.These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.