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.

Keywords:

• Ionizable lipids
• leukocytes
• lipid nanoparticles
• microfluidic mixing
• siRNA

Acknowledgements

This manuscript is dedicated to Prof. Pieter Cullis for all his achievements in the field of liposomal drug delivery. Specifically, we wish to convey our thanks to Pieter for his help in generating ionizable lipids and his outstanding collaboration over the years. We thank Prof. Terry Allen for reading the manuscript and for helpful suggestions. We also thank Dr. Stephanie Rietwyk, for assistance in manuscript preparation.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding information

This work was supported in part by grants from the NIH (5R01CA139444–10); The Dotan Hematology Center at Tel Aviv University; The Lewis Family Trust; the Israel Science Foundation (Award #181/10); the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant 41/11); the FTA: Nanomedicines for Personalized Theranostics of the Israeli National Nanotechnology Initiative; and by The Leona M. and Harry B. Helmsley Nanotechnology Research Fund (D.P.).