One of the main limitations in the use of nucleoside reverse transcriptase inhibitors (NRTIs) such as azidothymidine (AZT) lies in their poor intracellular activation by cellular kinases into their active tri-phosphorylated form. Thus, the direct administration of triphosphate NRTIs like azidothymidine-triphosphate (AZT-TP), has been considered for bypassing this metabolic bottleneck, but these molecules do not diffuse intracellularly, due to their too hydrophilic character. Therefore, poly(iso-butylcyanoacrylate) (PIBCA) aqueous-cored nanocapsules have been tested as carriers to overcome the cellular delivery of AZT-TP. However, encapsulation of AZT-TP remained challenging because this molecule, due to its relatively low molecular weight, rapidly leaked out of the nanocapsules. In this study, we show that association of AZT-TP to a cationic polymer such as poly(ethyleneimine) (PEI) allowed to reach high entrapment efficiency of AZT-TP in PIBCA nanocapsules (up to 90%) as well as gradual in vitro release. The resulting hybrid PIBCA/PEI nanocapsules efficiently delivered AZT-TP in vitro to macrophages: the cellular uptake was increased by 30-fold compared to the free molecule, reaching relevant cellular concentrations for therapeutic purposes.