Abstract
Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.
Highlights
For over a decade, the underlying obstacle preventing the widespread clinical use of small interfering RNA-based therapies has been efficient and safe in vivo delivery. siRNAs are large (∼14 kDa), polyanionic macromolecules that require extensive modifications to improve their inherently-poor pharmacological properties [1,2]
We present evidence suggesting that oligonucleotide hydrophobicity governs pharmacokinetic behavior by driving selective, in situ incorporation into endogenous lipoprotein pathways
To evaluate the impact of lipid conjugation on the pharmacological properties of oligonucleotides, we synthesized a panel of structurally diverse conjugates using a hydrophobically-modified siRNA scaffold, termed hsiRNA (Figure 1A, 1B) [9,10,15]
Summary
The underlying obstacle preventing the widespread clinical use of small interfering RNA (siRNA)-based therapies has been efficient and safe in vivo delivery. siRNAs are large (∼14 kDa), polyanionic macromolecules that require extensive modifications to improve their inherently-poor pharmacological properties (e.g. plasma half-life of
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