Current Progress in Non-viral RNAi-Based Delivery Strategies to Lymphocytes

Abstract

RNAi-based therapy holds great promise, as it can be utilized for the treatment of multiple conditions in an accurate manner via sequence-specific manipulation of gene expression. To date, RNAi therapeutics have advanced into clinical trials for liver diseases and solid tumors; however, delivery of RNAi to leukocytes in general and to lymphocytes in particular remains a challenge. Lymphocytes are notoriously hard to transduce with RNAi payloads and are disseminated throughout the body, often located in deep tissues; therefore, developing an efficient systemic delivery system directed to lymphocytes is not a trivial task. Successful manipulation of lymphocyte function with RNAi possesses immense therapeutic potential, as it will enable researchers to resolve lymphocyte-implicated diseases such as inflammation, autoimmunity, transplant rejection, viral infections, and blood cancers. This potential has propelled the development of novel targeted delivery systems relying on the accumulating research knowledge from multiple disciplines, including materials science and engineering, immunology, and genetics. Here, we will discuss the recent progress in non-viral delivery strategies of RNAi payloads to lymphocytes. Special emphasis will be made on the challenges and potential opportunities in manipulating lymphocyte function with RNAi. These approaches might ultimately become a novel therapeutic modality to treat leukocyte-related diseases.

Metal-organic frameworks for precise inclusion of single-stranded DNA and transfection in immune cells

“…Intracellular delivery of biomolecules is essential in biological research and therapeutic applications and gene editing 39 – 44 . One of the major obstacles for their clinical application is the lack of safe, efficient and low-cost delivery methods 39 , 40 , especially for stem cells and immune cells, which are the most difficult to transfect but also the most exciting target cell types in gene therapy 39 , 42 , 43 . Despite high delivery efficiency, existing viral method suffers from safety concern, high cost, and scale-up difficulty 39 , 40 .…”

A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

“…Efficient delivery of RNAi molecules into cells is a crucial determinant for the effective regulation of target genes [21,22]. Viral vectors and non-viral nanoparticulate systems are most commonly used vehicles for the delivery of RNAi molecules [23][24][25]. Viral vectors represent the most efficient gene delivery vehicles; however, their immunogenicity and toxicity limit their clinical use [26].…”

RNA Interference Therapies for an HIV-1 Functional Cure

“…They would also open up several new targets for combination HIV-1 drug therapy. A major challenge for the development of anti-HIV-1 siRNAs is that lymphocytes, which represent the major cell-type for HIV-1 replication, are widely distributed in the body and extremely difficult to penetrate with existing siRNA delivery technologies (reviewed in [ 127 ]). To compete with current HIV-1 drug therapies, anti-HIV-1 siRNAs will need to have a long shelf life, be delivered orally and bring viral loads to undetectable levels with at least a once daily dose.…”