Abstract
Incorporating multiple copies of two RNAi molecules into a single nanostructure in a precisely controlled manner can provide an efficient delivery tool to regulate multiple gene pathways in the relation of mutual dependence. Here, we show a RNA nanotechnology platform for a two-in-one RNAi delivery system to contain polymeric two RNAi molecules within the same RNA nanoparticles, without the aid of polyelectrolyte condensation reagents. As our RNA nanoparticles lead to the simultaneous silencing of two targeted mRNAs, of which biological functions are highly interdependent, combination therapy for multi-drug resistance cancer cells, which was studied as a specific application of our two-in-one RNAi delivery system, demonstrates the efficient synergistic effects for cancer therapy. Therefore, this RNA nanoparticles approach has an efficient tool for a simultaneous co-delivery of RNAi molecules in the RNAi-based biomedical applications, and our current studies present an efficient strategy to overcome multi-drug resistance caused by malfunction of genes in chemotherapy.
Highlights
Incorporating multiple copies of two RNAi molecules into a single nanostructure in a precisely controlled manner can provide an efficient delivery tool to regulate multiple gene pathways in the relation of mutual dependence
RNA nanoparticles for simultaneous co-delivery of MDR1 siRNA and BCL2 siRNA, we first designed linear DNA template, which could be transcribed into RNA transcripts via rolling circle transcription (RCT) reaction, in a way that both siRNA sequences alternated with each other (Fig. 1A and Supplementary Table S1)
Using T7 RNA polymerase-mediated RCT reaction against the resulting closed DNA template, we generated RNA transcripts (Dsi RNA transcripts or Dsi RNAtr), of which multiple tandem repeats of RNA hairpins contained the alternate sequences of siMDR1 and siBCL2
Summary
Incorporating multiple copies of two RNAi molecules into a single nanostructure in a precisely controlled manner can provide an efficient delivery tool to regulate multiple gene pathways in the relation of mutual dependence. As our RNA nanoparticles lead to the simultaneous silencing of two targeted mRNAs, of which biological functions are highly interdependent, combination therapy for multi-drug resistance cancer cells, which was studied as a specific application of our two-inone RNAi delivery system, demonstrates the efficient synergistic effects for cancer therapy. To further expand versatility of these RNA nanoparticles in the therapeutic applications, the goal was to develop a two-in-one RNA NPs delivery system that simultaneously delivers two types of siRNAs for potent synergistic therapies based on RNAi. As regards chemotherapy failure in the cancer treatment, the intrinsic or acquired drug resistance of cancer cells is often affected by multiple gene pathways that are highly interdependent, and eventually reduces the cytotoxic effects of anticancer drugs, resulting in a relapse of cancer[4]. There still remain many problems for delivering siRNA to tumors in vitro or in vivo, including the tricky cellular uptake, low loading efficacy for siRNA cargo, unsafety in the immune system, instability in bloodstream, and lack of targeting ability[19]
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