Nano Research & Applications

A modular platform for targeted RNAi therapeutics using biologically-lipidated antibodies

EuroSciCon Conference on Nanotech & Nanobiotechnology Nano
July 12-13, 2018 Paris , France

Itai Benhar, Ranit Kedmi, Nuphar Veiga, Limor Nahary, Edo Kon, Meir Goldsmith, Dan Rosenblum, Shani Leviatan-Ben-Arye and Dan Peer

Tel Aviv University, Israel

Posters & Accepted Abstracts: Nano Res Appl

DOI: 10.21767/2471-9838-C2-012

Abstract

Small interfering (si) RNAs can be used to silence disease-causing genes. However, their development as drugs has been limited mainly in knocking down liver gene expression, since delivery to other tissues requires development of a targeted delivery carrier. Modulating immune cells function using siRNAs holds great promise in advancing targeted therapies to many immunerelated disorders including cancer, inflammation, autoimmunity, and viral infections. However, the ability to effectively knockdown gene expression in leukocytes is still challenging. Here, we present a modular platform to target specific cell types, exemplified here with immune cells, using siRNA loaded lipid nanoparticles (LNP) coated with oriented, targeting antibodies noncovalently bound to a membrane-anchored lipoprotein that recognizes their Fc domain. Unlike chemically conjugated antibodies, these oriented antibodies maintain their high affinity and the LNPs avoid scavenging by Fc receptors on macrophages. A simple switch in 5 different targeting antibodies (against Ly6C, CD3, CD4, CD25 and Itgb7) redirected the LNP for exquisitely specific uptake in diverse leukocyte subsets in vivo and enabled specific knockdown in difficult-to-transfect CD4+ cells. Intravenously injected anti- Ly6C-coated LNP encapsulating TNF siRNAs were taken up selectively by Ly6C+ monocytes and activated tissue macrophages, suppressed TNF-α expression in the colon and ameliorated inflammatory bowel disease symptoms in a DSS-induced colitis mouse model, demonstrating the platform’s potential therapeutic utility. This approach opens new avenues for studying cell biology in vivo and potentially for a wide range of therapeutic applications in a cell-specific manner.