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RNA interference via small interfering RNA (siRNA) has many potential therapeutic applications, and liposomal-based systems are useful for improving the pharmacokinetics of siRNAs, including their intracellular release and distribution. However, for the successful translation of this technology into clinical applications, it is important to understand how liposomal encapsulation changes the cellular uptake and immunostimulatory adverse effects of siRNAs. Here we evaluated the cellular uptake and innate immune activation by an immunostimulatory siRNA encapsulated within a liposome carrier in commercially available human peripheral blood mononuclear cells (PBMCs). We found considerable lot-to-lot variation in cytokine production by the PBMCs. Flow cytometric analysis in conjunction with intracellular staining of tumor necrosis factor-α (TNF-α) revealed that after treating PBMCs with the liposomal siRNA, approximately 5% of the cells produced TNF-α and more than 90% of the TNF-α-producing cells were positive for CD14 expression. We also showed that peripheral blood CD14 + monocytes in the cytokine release assay had low inter-lot variabilities in TNF-α production, suggesting that the peripheral blood CD14 + monocyte-based cytokine release assay is a specific means of alleviating the lot-to-lot variability in the cytokine release profiles of commercially available PBMCs. Our results also show that the peripheral blood CD14 + monocyte-based cytokine release assay can be used to identify the siRNA recognition receptors that mediate individual cytokine production.

Cell Type-Specific Responses of Peripheral Blood CD14-Positive Monocytes to Liposome-Encapsulated Immunostimulatory siRNA