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Objective: In order to improve the water solubility and bioavailability of curcumin in cancer therapy, we prepared and tested a novel waterborne cationic polyurethane (PU) as a nano-carrier for curcumin loading (CU-PU). We studied the effect of this prepared nano-drug on melanoma (F10B16) and fibroblasts cells (L929). Methods: Morphology, size and cell internalization ability of the prepared nanoparticles were analyzed by zetasizer, SEM, AFM and fluorescent microscopy, respectively. We anticipated that curcumin was loaded in the hydrophobic core of the PU carrier. Next, the suitable dose and therapeutic effects of CU-PU for both skin cancer and normal cell lines were evaluated by the MTT assay and real-time PCR. Results: The average diameters and polydispersity of the nanoparticles were 62.37 ± 1.7 nm and 0.080 ± 2.1 at 25 °C, respectively. The drug encapsulation efficiency was 87 ± 0.2%. The morphological analysis confirmed both a spherical shape and good dispersion without remarkable aggregation. The MTT assay results showed that the IC50 at 24 hours was 36.2 μM, whereas it was 25.4 μM at 48 hours. Real-time PCR results indicated that the CU-PU significantly decreased mRNA expressions of VEGF, Bcl-2, MMP-9 and COX-2 genes. An increase in mRNA expression of the BAX gene was also observed. Conclusion: Our result provided acceptable evidence for cell proliferation inhibition and the apoptotic effect of CU-PU on skin cancer cells. There were no adverse effects detected for normal cells. [ABSTRACT FROM AUTHOR]