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Ever since the ground breaking discovery of RNA interference (RNAi), an endogenous mechanism for sequence specific regulation of gene expression via short interfering RNAs (siRNA), researchers and pharmaceutical companies alike have devoted immense time and capital into the design of nanocarriers that can mediate safe and effective delivery. After over a decade of research, a PubMed search for ‘siRNA delivery’ returns over 2500 references, yet only a handful of delivery systems have been successfully translated to the clinic. This low rate of clinical translation can partly be attributed to the complexity of the barriers that need to be overcome in vivo. Advances in identifying some of these barriers have lead to the development of molecular components that can overcome some of these hurdles. The judicious assembly of these components, as seen in stable nucleic-acid–lipid nanoparticles and the cyclodextrin polymer, will be required for the successful clinical translation of nanoparticle-based siRNA therapeutics.