Biodegradable dextran nanogels as functional carriers for the intracellular delivery of small interfering RNA

RNA interference (RNAi) certainly is a hot topic among the scientific community, judging by the broad financial investments and the tremendous research output to date.[1] This statement is further illustrated through a PubMed search on the term ‘RNA interference’ (performed on June 15th 2009), which yielded ~16.500 entries. RNAi is a naturally conserved gene silencing mechanism functioning in eukaryotic cells and is activated by small interfering RNAs (siRNAs) that trigger the degradation of mRNA in a sequence‐specific manner. Besides its use as a laboratory tool in functional genomics and drug target discovery, the therapeutic potential of RNAi by blocking the production of disease‐causing proteins has also long been recognized. In conclusion, this thesis comprises a novel FRET based approach for the intracellular assessment of small interfering RNA (siRNA) integrity, which could aid in clarifying the correlation between intracellular siRNA fate and the eventual RNAi outcome. Besides siRNA stability, this thesis also describes the design of cationic and biodegradable nanogels for the time‐controlled delivery of siRNA. We provide evidence that these nanogels can effectively deliver active siRNA across the cellular barrier, leading to substantial and durable gene silencing. Endosomal escape is identified as the predominant barrier confining the full RNAi potential, opening up new opportunities to further improve this delivery concept. It is conceivable that, although RNAi can generally be applied to interfere with the expression of virtually any gene, several distinct in vivo delivery agents will be needed depending on the disease target and the chosen route of administration. Our nanogels may well claim a future position in this ensemble of siRNA delivery systems.