The direct delivery of immunomodulatory agents into T cells to control the immunosuppressive TME in melanoma was carried out applying cationic lipid-assisted PEG–PLA-based nanoparticles delivering siRNA into T cells in vitro. The results demonstrated reduced CTLA-4 mRNA and protein levels and activation of T cells as well as increased percentage of effector CD4+ T cells and CD8+ T cells and decreased ratio of CD4+ FOXP3+ Tregs inhibiting tumor growth and prolonged survival time in mice with melanoma (153). The gene discussed is CTLA4; the disease is melanoma.