Lymphocytes are the gatekeepers of the body's immune system and are involved in pathogenesis if their surveillance is stalled by inhibitory molecules or when they act as mediators for viral entry. Engineering lymphocytes in order to restore their functions is an unmet need in immunological disorders, cancer and in lymphotropic viral infections. Recently, the FDA approved several therapeutic antibodies for blocking inhibitory signals on T cells. This has revolutionized the field of solid tumor care, together with chimeric antigen receptor T cell (CAR-T) therapy that did the same for hematological malignancies. RNA interference (RNAi) is a promising approach where gene function can be inhibited in almost all types of cells. However, manipulation of genes in lymphocyte subsets are difficult due to their hard-to-transfect nature and in vivo targeting remains challenging as they are dispersed throughout the body. The ability of RNAi molecules to gain entry into cells is almost impossible without delivery strategy. Nanotechnology approaches are rapidly growing and their impact in the field of drug and gene delivery applications to transport payloads inside cells have been extensively studied. Here we discuss various technologies available for RNAi delivery to lymphocytes. We shed light on the importance of targeting molecules in order to target lymphocytes in vivo. In addition, we discuss recent developments of RNAi delivery to lymphocyte subsets, and detail the potential implication for the future of molecular medicine in leukocytes implicated diseases.