We report a potentially general solution to the grand challenge of delivering siRNA in vitro and in vivo. RNA interference (RNAi) represents a transformative approach to biochemical pathway analysis, diagnostics, imaging, drug discovery and therapy. However, the poly-charged nature of oligonucleotides and their enzymatic degradation present challenges for the widespread use of siRNA as biological tools and therapy. To address this problem, we designed and synthesized guanidinium-rich amphipathic oligocarbonates which noncovalently complex, deliver, and release siRNA, resulting in up to 90% knockdown of target proteins. The organocatalytic oligomerization to access these co-oligomers is step-economical, remarkably versatile for the design and discovery of siRNA delivery vehicles, and affords an exceptionally quick strategy to explore chemical space and optimize siRNA delivery. The versatility of this approach, and the biodegrability of the designed agents make this an attractive strategy for therapy and biological tool development.

siRNA complexation, delivery, and release by new biodegradable molecular transporters

243rd National Meeting (2012)

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