Abstract: To investigate the effect that folic acid-modified polyrotaxanes (FPP) transfered siRNA CD47 to inhibit melanoma proliferation, the expression of CD47 in clinical melanoma patients was tested by Western blot and RT-PCR, respectively. Physical performance of FPP (siRNA-CD47:CD47) nanoparticles was tested by Malvern particle size instrument and scanning electron microscope. The clone formation experiment demonstrated that FPP (CD47) nanoparticles inhibited the growth of clones. Invasion assay revealed that FPP (CD47) inhibited migration of B16F10 cells. Tumor bearing mice were used in the experiment to test the efficacy of FPP (CD47) treatment. Compared with the control group, high expression of CD47 was observed in the clinical melanoma patients. FPP (CD47) nanoparticle size at 80 nm exhibited a potential of 10 mV; compared with FPP (Con), fluorescence intensity was significantly reduced to 4.2% and B16F10 cell clone formation was decreased by 91% in the FPP (CD47) treatment. Tumor volume of tumor-burdened mice was decreased by 90% with FPP (CD47) treatment. FPP (CD47) lowered CD47 protein and mRNA expression in the tumor. This study suggests that FPP may transfer siRNA CD47 into the cancer cells to inhibit melanoma growth effectively.