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Self-assembled RNA interference microsponges for efficient siRNA delivery


The encapsulation and delivery of short interfering RNA (siRNA) has been realized using lipid nanoparticles1,2, cationic complexes3,4, inorganic nanoparticles5,6,7,8, RNA nanoparticles9,10 and dendrimers11. Still, the instability of RNA and the relatively ineffectual encapsulation process of siRNA remain critical issues towards the clinical translation of RNA as a therapeutic1,12,13. Here we report the synthesis of a delivery vehicle that combines carrier and cargo: RNA interference (RNAi) polymers that self-assemble into nanoscale pleated sheets of hairpin RNA, which in turn form sponge-like microspheres. The RNAi-microsponges consist entirely of cleavable RNA strands, and are processed by the cell’s RNA machinery to convert the stable hairpin RNA to siRNA only after cellular uptake, thus inherently providing protection for siRNA during delivery and transport to the cytoplasm. More than half a million copies of siRNA can be delivered to a cell with the uptake of a single RNAi-microsponge. The approach could lead to novel therapeutic routes for siRNA delivery.

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Figure 1: Schematic showing the process of rolling circle transcription (RCT) for the self-assembled RNAi-microsponge.
Figure 2: Characterization of the RNAi-microsponge.
Figure 3: Formation of sponge-like spherical structures purely with RNA strands.
Figure 4: Generating siRNA from RNAi-microsponges by the RNAi pathway, and condensing RNAi-microsponges for transfection.
Figure 5: Transfection and gene silencing effect.

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Supported by the National Institutes of Health (NIH) NIBIB Grant R01-EB008082, an American Recovery and Reinvestment (ARRA) grant, the National Science Foundation Grant, Division of Materials Research Polymers Program #0705234 and a Nanotechnology grant from the Koch Institute for Integrative Cancer Research. We also thank the Institute for Soldier Nanotechnologies (ISN) and Center for Materials Science Research (CMSE) for use of facilities.

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J.B.L. and P.T.H. designed the experiments. J.B.L., J.H., D.K.B. and Z.P. carried out experiments. J.B.L., J.H., D.K.B., Z.P. and P.T.H. contributed to analysis of the data. J.B.L. and P.T.H. wrote the manuscript.

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Correspondence to Jong Bum Lee, Zhiyong Poon or Paula T. Hammond.

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The authors declare no competing financial interests.

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Lee, J., Hong, J., Bonner, D. et al. Self-assembled RNA interference microsponges for efficient siRNA delivery. Nature Mater 11, 316–322 (2012).

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