Editors' ChoiceNanomedicine

Carrier and Therapeutic in One

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Science Translational Medicine  25 Apr 2012:
Vol. 4, Issue 131, pp. 131ec71
DOI: 10.1126/scitranslmed.3004179

One style of children’s toy involves a seemingly plain carrying case that opens up (surprise!) to reveal that the case is in fact the toy itself. Backpacks that turn inside out to form teddy bears, cases that open up to reveal secret worlds, or even the game of backgammon make delightful use of this concept. For the delivery of short interfering RNA (siRNA) therapeutics, which are used to turn down expression of target genes, carriers have long been used in the form of condensing agents that can protect and deliver the therapeutic payload into desired cells. However, such carriers have a history of toxicity, low loading efficiencies, and at times complicated multistep syntheses. Now, Lee and co-workers describe microparticle carriers for siRNA that, once delivered to cells, transform directly from the carrier into the siRNA therapeutic itself, like a child’s carrying case opening to reveal that it is an unexpected toy.

The strategy is based on using RNA as the carrier material; it takes advantage of the RNA synthetic method of rolling circle transcription to enzymatically produce elongated and pure RNA strands that contain multiple copies of the therapeutic siRNA sequences within them. These long strands self-assemble into 2-μm-diameter, crystalline spherical particles with a highly convoluted topology, which were termed “microsponges” because of their sponge-like appearance. Simply coating these microsponges with a polycation reduced particle size and promoted cellular uptake. Upon delivery, intracellular RNA-processing enzymes, including Dicer and the RNA-induced silencing complex, cleaved the microsponges into siRNAs that could then silence specific genes. The authors illustrated this concept by knocking down expression of a luciferase reporter in cell cultures and in mouse tumors.

This approach of producing concentrated RNA therapeutics and protecting them from degradation by virtue of their own assembly may be a cost-effective approach compared with techniques in which siRNAs are loaded into carriers. Indeed, Lee and colleagues report that they were able to deliver the same transfection efficiency with a siRNA particle concentration that was three orders of magnitude below that typically used with commercially available nanoparticle-based delivery systems. Such practical considerations may have important implications for the production of commercially viable siRNA therapies.

J. B. Lee et al., Self-assembled RNA interference microsponges for efficient siRNA delivery. Nat. Mater. 11, 316–322 (2012). [Abstract]

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