HIV is one of the deadliest pandemics of modern times, having already caused 35 million deaths around the world. Despite thehuge efforts spent to develop treatments, the virus cannot yet be eradicated and continues to infect new people. Spread of thevirus remains uncontrolled, thus exposing the worldwide population to HIV danger, due to the lack of efficient vaccines. The latestclinical trials describe the challenges associated with developing an effective prophylactic HIV vaccine. These immunologicalobstacles will only be overcome by smart and innovative solutions applied to the design of vaccine formulations. Here, we describethe use of nanostructured lipid carriers (NLC) for the delivery of p24 protein as a model HIV antigen, with the aim of increasing itsimmunogenicity. We have designed vaccine formulations comprising NLC grafted with p24 antigen, together with cationic NLCoptimized for the delivery of immunostimulant CpG. This tailored system significantly enhanced immune responses against p24, interms of specific antibody production and T-cell activation in mice. More importantly, the capacity of NLC to induce specificimmune responses against this troublesome HIV antigen was further supported by a 7-month study on non-human primates (NHP).This work paves the way toward the development of a future HIV vaccine, which will also require the use of envelope antigens.