Structurally modulated codelivery of siRNA and Argonaute 2 for enhanced RNA interference
Abstract
Small interfering RNA (siRNA) has great potential to specifically target undruggable genes in many diseases. Despite its great promise, few siRNAs have been clinically approved due to limited therapeutic efficacy. We propose that one major barrier to RNA interference (RNAi)-based therapy is that the siRNA must form a bound complex with a “scissor” protein, Argonaute 2 (Ago2), after it is released in the cytoplasm. We take the approach of preassembling the duplex siRNA with Ago2 protein, and then packaging the complex with commercial transfection reagents or structurally defined polycations that specifically enhance the clustering of siRNA with Ago2. This unique approach augments gene silencing in cell lines and a melanoma mouse model, providing a potential translatable platform for RNAi therapies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 05, 2018
- Source ID
- 10.1073/pnas.1719565115
Entities
People
- Connie Wu
- Elad Elkayam
- Jiahe Li
- Leemor Joshua-tor
- Paula T. Hammond
- Wade Wang
- Yanpu He
Organizations
- Howard Hughes Medical Institute
- Massachusetts Institute of Technology
- United States Department of Defense