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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.

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