In Vivo Delivery of RNAi by Reducible Interfering
Nanoparticles (iNOPs)
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Abstract
RNA interference (RNAi) has considerable
potential as a therapeutic
strategy, but the development of efficient in vivo RNA delivery methods
remains challenging. To this end, we designed and synthesized chemically
modified interfering nanoparticles (iNOPs) composed of functionalized
poly-l-lysine dendrimers modified with reducible spacers
to facilitate release of small interfering RNAs (siRNAs) in vivo.
We show that the novel siRNA–iNOP complexes mediate efficient
gene-specific RNAi in cultured cells and in mice, where they display
enhanced tissue-targeting capabilities. At a clinically feasible dose
of 1 mg kg<sup>–1</sup>, apolipoprotein B (apoB) siRNA–iNOP
complexes achieved ∼40–45% reduction of liver apoB mRNA
and plasma apoB protein levels within 48 h of administration to mice,
without apparent toxicity. Collectively, these findings demonstrate
that siRNA delivery by the modified reducible iNOPs can provide a
clinically significant and potentially tissue-specific new approach
for RNAi therapy