Cancer cells are aided by immune-tolerant functions of HLA-G to escape the immune surveillance. In general, cancer cells can express membranous HLA-G, secrete soluble HLA-G, produce HLA-G positive exosomes, and can be subjected to proteolytic cleavage by matrix metalloproteinases releasing shedding HLA-G1 in stressful conditions. Thus, the downregulation of HLA-G either in transcripts or proteins may affect positively cancer therapy. The aim of this study was to examine the molecular nanoparticles targeting HLA-G. Special focus was accorded to RNA interference particles. Although numerous studies have reported the importance of HLA-G gene expression modulation by nanoparticles, no studies have investigated clinically their efficiency in this modulation.