title: Advances in RNAi therapeutic delivery to leukocytes using lipid nanoparticles.
abstract: Small interfering RNAs (siRNAs) therapeutics has advanced into clinical trials for liver diseases and solid tumors, but remain a challenge for manipulating leukocytes fate due to lack of specificity and safety issues. Leukocytes ingest pathogens and defend the body through a complex network. They are also involved in the pathogeneses of inflammation, viral infection, autoimmunity and cancers. Modulating gene expression in leukocytes using siRNAs holds great promise to treat leukocyte-mediated diseases. Leukocytes are notoriously hard to transduce with siRNAs and are spread throughout the body often located deep in tissues, therefore developing an efficient systemic delivery strategy is still a challenge. Here, we discuss recent advances in siRNA delivery to leukocyte subsets such as macrophages, monocytes, dendritic cells and lymphocytes. We focus mainly on lipid-based nanoparticles (LNPs) comprised of new generation of ionizable lipids and their ability to deliver siRNA to primary or malignant leukocytes in a targeted manner. Special emphasis is made on LNPs targeted to subsets of leukocytes and we detail a novel microfluidic mixing technology that could aid in changing the landscape of process development of LNPs from a lab tool to a potential novel therapeutic modality.
authors.affiliation: a Laboratory of NanoMedicine, Department of Cell Research and Immunology , George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv , Israel.|b Department of Materials Science and Engineering, The Iby and Aladar Fleischman Faculty of Engineering , Tel Aviv University , Tel Aviv , Israel.|c Center for Nanoscience and Nanotechnology , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramishetti
authors.affiliation: a Laboratory of NanoMedicine, Department of Cell Research and Immunology , George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv , Israel.|b Department of Materials Science and Engineering, The Iby and Aladar Fleischman Faculty of Engineering , Tel Aviv University , Tel Aviv , Israel.|c Center for Nanoscience and Nanotechnology , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Landesman-Milo
authors.affiliation: a Laboratory of NanoMedicine, Department of Cell Research and Immunology , George S. Wise Faculty of Life Sciences, Tel Aviv University , Tel Aviv , Israel.|b Department of Materials Science and Engineering, The Iby and Aladar Fleischman Faculty of Engineering , Tel Aviv University , Tel Aviv , Israel.|c Center for Nanoscience and Nanotechnology , Tel Aviv University , Tel Aviv , Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
mesh_terms: D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D034622:RNA Interference
chemical_list: D008055:Lipids
keywords: Ionizable lipids; leukocytes; lipid nanoparticles; microfluidic mixing; siRNA