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RAMOT at Tel Aviv University Ltd. posted this:

Modulating T cells functions by down regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune related disorders including cancer, inflammation, autoimmunity and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4+ T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface functionalized with anti-CD4 monoclonal antibody (mAb) to permit delivery of the siRNAs specifically to CD4+ T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4+ T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4+ T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood and the bone marrow. Silencing by tLNPs occur in a subset of circulating and resting CD4+ T lymphocytes. Interestingly, we show that tLNPs internalization and not endosome escape is a fundamental event that takes place as early as one hour after systemic administration that determine tLNPs efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases. Project ID : 10-2016-962