The current paradigm in the development of new cancer therapies is the ability to target tumor cells while avoiding harm to noncancerous cells. Furthermore, there is a need to develop novel therapeutic options against drug-resistant cancer cells. Herein, we characterized the placental-derived stem cell (PLSC) exosomes (PLSCEXO) and evaluated their anti-cancer efficacy in prostate cancer (PCa) cell lines. Nanoparticle tracking analyses revealed the size distribution (average size 131.4 +/- 0.9 nm) and concentration of exosomes (5.23 x 10(10)+/- 1.99 x 10(9) per ml) secreted by PLSC. PLSCEXO treatment strongly inhibited the viability of enzalutamide-sensitive and-resistant PCa cell lines (C4-2B, CWR-R1, and LNCaP cells). Interestingly, PLSCEXO treatment had no effect on the viability of a non-neoplastic human prostate cell line (PREC-1). Mass spectrometry (MS) analyses showed that PLSCEXO are loaded with 241 proteins and mainly with saturated fatty acids. Further, Ingenuity Pathway Analysis analyses of proteins loaded in PLSCEXO suggested the role of retinoic acid receptor/liver x receptor pathways in their biological effects. Together, these results suggest the novel selective anti-cancer effects of PLSCEXO against aggressive PCa cells. (C) 2018 Elsevier Inc. All rights reserved.