Delivery strategies of RNA therapeutics for ex vivo and in vivo B-cell malignancies

B-cell malignancies are among the most common hematological malignancies and are characterized by B-lymphocyte proliferation and accumulation in the bloodstream or lymphatic organs. Genetic abnormalities contribute tremendously to the initiation and maintenance of these diseases, by chromosomal translocations, acquired mutations that contribute to cancer prosperity, or both. RNAi-based therapy holds great promise for revolutionizing cancer therapeutics, as it can be utilized for sequence-specific genetic manipulation in multiple conditions. Therefore, altering the genetic expression of lymphocytes with RNAi has immense therapeutic potential for the therapy of hematological malignancies. Thus far, systemic delivery of RNAi to the liver has reached the clinic, and numerous clinical trials for liver diseases and solid tumors are under evaluation; yet, systemic delivery of RNAi to lymphocytes remains challenging. Lymphocytes exhibit low transfection efficiencies when using conventional transfection agents and are dispersed throughout the body, sometimes embedded deep within tissues, making delivery and internalization of RNA payload into lymphocytes a notorious task. In this chapter, we discuss the challenges in lymphocyte manipulation with RNAi and describe the nonviral RNAi-delivery systems to B-lymphocytes. We focus on delivery strategies that show efficacy in targeting malignant B-lymphocytes ex vivo and in vivo.