Development of a Modular Ribonucleoprotein Complex as a General Strategy to Deliver RNAi Therapeutics

Abstract RNAi therapeutics can potentially address undruggable diseases. However, their full potential is stymied by delivery challenges. An siRNA delivery platform by remodeling the human U4 small nuclear ribonucleoprotein complex (snRNP) is developed. This remodeled protein‐siRNA complex (SmiRNP) serves as a biocompatible, modular, and customizable platform for attaching desired functional modules to overcome delivery hurdles. Here, it is demonstrated that the SmiRNP complex, by using siRNA against KRAS as a proof of principle, can deliver the siRNA into cells and protect it from nuclease degradation, allowing the siRNA to knockdown KRAS mRNA and protein levels, reduce cancer cell viability, and suppress tumor growth in vivo. This general strategy allows many more modular combinations and would enable the delivery of a wide spectrum of RNAi therapeutics.