Ligand-mediated delivery of RNAi-based therapeutics for the treatment of oncological diseases

Abstract

RNA interference (RNAi)-based therapeutics (miRNAs, siRNAs) have great potential for treating various human diseases through their ability to downregulate proteins associated with disease progression. However, the development of RNAi-based therapeutics is limited by lack of safe and specific delivery strategies. A great effort has been made to overcome some of these challenges resulting in development of N-acetylgalactosamine (GalNAc) ligands that are being used for delivery of siRNAs for the treatment of diseases that affect the liver. The successes achieved using GalNAc-siRNAs have paved the way for developing RNAi-based delivery strategies that can target extrahepatic diseases including cancer. This includes targeting survival signals directly in the cancer cells and indirectly through targeting cancer-associated immunosuppressive cells. To achieve targeting specificity, RNAi molecules are being directly conjugated to a targeting ligand or being packaged into a delivery vehicle engineered to overexpress a targeting ligand on its surface. In both cases, the ligand binds to a cell surface receptor that is highly upregulated by the target cells, while not expressed, or expressed at low levels on normal cells. In this review, we summarize the most recent RNAi delivery strategies, including extracellular vesicles, that use a ligand-mediated approach for targeting various oncological diseases.

Attenuation of Excess TNF-α Release in Crohn’s Disease by Silencing of iRHOMs 1/2 and the Restoration of TGF-β Mediated Immunosuppression Through Modulation of TACE Trafficking

“…In the future, we plan to test the efficacy of the iRHOM siRNA treatments in vivo and optimize drug delivery. Several studies have indicated that iron scavenging receptors, such as SCARA5, are upregulated on the surfaces of MAP-infected macrophages ( 39 – 41 ). Therefore, if we conjugate ferritin to the iRHOM siRNAs, this should effectively deliver the treatment to the cytosol of the effected cells ( 40 ).…”

MicroRNA-34a, Prostate Cancer Stem Cells, and Therapeutic Development

“…Current delivery systems of miR-34a mainly utilize the packaged vehicle strategy [ 14 ]. The other platform is unpackaged or ligand-conjugates, such as folate [ 65 , 66 ]. Despite extensive research in the field, the translation of miR-34a therapeutics into the clinic has been hindered by several issues including delivery vehicle-associated toxicity, inefficient cellular uptake and serum stability, and limited specificity to targeted tumors.…”

“…Despite extensive research in the field, the translation of miR-34a therapeutics into the clinic has been hindered by several issues including delivery vehicle-associated toxicity, inefficient cellular uptake and serum stability, and limited specificity to targeted tumors. The stability problem is due to the sensitivity of unmodified miR-34a oligos to nuclease-mediated degradation, thereby requiring repetitive cycles of high-dose to achieve the desired therapeutic response [ 66 ]. Thus, chemical modifications have been pursued to overcome the issue ( Figure 1 , right).…”

Extracellular Vesicles and Hepatocellular Carcinoma: Opportunities and Challenges

“…The pathway of EVs internalization determines the functional response and efficiency of cargo delivery, while the internalization of EVs is mediated by a variety of mechanisms ( 80 ), including grid protein dependence and endocytosis of grid protein non-dependent pathways ( 78 ). In general, endocytosis is usually divided into two main subgroups: phagocytosis and cytokinesis.…”

“…Non-dependent endocytosis of grid proteins, including the formation of inverted influxes of vesicle-coated cells on cell membranes ( 77 , 84 , 85 ). Alternatively, fusing with the exoplasmic membrane, EVs can enter cell directly, thereby release their contents into the cytoplasm ( 80 ).…”