Systemic delivery of RNA interference (RNAi) payloads for manipulation of gene expression in lymphocytes holds a great potential as a novel therapeutic modality for hematological malignancies and autoimmune disorders. However, lymphocytes are among the most difficult cells to transfect with RNAi, as they are resistant to conventional transfection reagents and are dispersed throughout the body, making it a challenge to successfully deliver these payloads via systemic administration route. We have developed a strategy to target lymphocytes and deliver RNAi payloads in a cell-specific manner to induce therapeutic gene silencing. This approach utilizes antibodies that decorate lipid nanoparticle surfaces to home into lymphocyte subsets. This approach opens new avenues for discovery of new drug targets and potentially for therapeutics.