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Antimonials are first\u2010line drugs due to resistance and side effects there is a demand for alternative chemotherapy. Itraconazole (ITZ) is an antimycotic. It was encapsulated into poly(lactic\u2010<jats:italic>co<\/jats:italic>\u2010glycolic acid) (PLGA) nanoparticles (NPs) and covered with mannose. The NPs were 250 nm and \u22121.1 mV\u2009\u00b1\u20090.7. PLGA\u2010ITZ\u2010mannose NPs presented a toxicity of 20.7% for J774 cells, and no toxicity for THP 1. The J774 cells were infected with three <jats:italic>Leishmania<\/jats:italic> promastigotes strains and treated with ITZ loaded PLGA NPs with\/without mannose. The parasite percentage of <jats:italic>L.(V.) panamensis<\/jats:italic> intracellular amastigotes significantly (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) decreased from 34.4% to 13.7% and 5.7% for PLGA\u2010ITZ\u2010mannose NPs and PLGA\u2010ITZ NPs, respectively. For <jats:italic>L.(L.) infantum<\/jats:italic> there was a reduction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) from 18.1% to 4.8% and 8.3% for PLGA\u2010ITZ\u2010mannose NPs and PLGA\u2010ITZ NPs, respectively. Further with <jats:italic>L.(L.) braziliensis<\/jats:italic> amastigotes there was a significant reduction (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) from 54.9% to 28% and 21.1% for PLGA\u2010ITZ\u2010mannose NPs and PLGA\u2010ITZ NPs, respectively. Adding mannose increased the efficacy PLGA\u2010ITZ NPs against <jats:italic>L.(L.) infantum<\/jats:italic>, while it had no effect against <jats:italic>L(V.) panamensis<\/jats:italic> and <jats:italic>L.(L.) braziliensis<\/jats:italic> amastigotes. We recommend further investigation of PLGA\u2010ITZ\u2010mannose NPs in animal models to evaluate their potential. \u00a9 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 00B: 000\u2013000, 2018. \u00a9 2018 Wiley Periodicals, Inc. 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