Self-assembled RNA interference microsponges for efficient siRNA delivery

siRNA delivery has so far been hampered by carriers that inefficiently encapsulate RNA, and by its degradation prior to cellular uptake. Now, self-assembled crystalline microsponges consisting solely of cleavable RNA strands — which are converted to siRNA only after cellular uptake — achieve, with three orders of magnitude lower concentration, the same degree of gene silencing as conventional siRNA nanocarriers. 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.