Abstract
The world-first success of lipid nanoparticle (LNP)-based siRNA therapeutics (ONPATTRO®) promises to accelerate developments in siRNA therapeutics/gene therapy using LNP-type drug delivery systems (DDS). In this study, we explore the optimal composition of an LNP containing a self-degradable material (ssPalmO-Phe) for the delivery of oligonucleotides. siRNA or antisense oligonucleotides (ASO) were encapsulated in LNP with different lipid compositions. The hepatic knockdown efficiency of the target genes and liver toxicity were evaluated. The optimal compositions for the siRNA were different from those for ASO, and different from those for mRNA that were reported in a previous study. Extracellular stability, endosomal escape and cellular uptake appear to be the key processes for the successful delivery of mRNA, siRNA and ASO, respectively. Moreover, the compositions of the LNPs likely contribute to their toxicity. The lipid composition of the LNP needs to be optimized depending on the type of nucleic acids under consideration if the applications of LNPs are to be further expanded.
Highlights
Gene silencing using synthetic oligonucleotides such as a small-interfering RNA or an antisense oligonucleotide (ASO) is a promising approach for suppressing the expression of pathogenic proteins in cells/tissues
We explored the optimal composition of LNPssPalmO-Phe for the hepatic delivery of small-interfering RNA (siRNA) by monitoring the membrane destabilizing ability of the system (LNPssPalmO-Phe –siRNA), and the resulting lipid nanoparticle (LNP) formulation was used for ASO delivery (LNPssPalmO-Phe –ASO)
The findings reported reveal that the encapsulation of ASO in LNPssPalmO-Phe significantly improved the knockdown efficiency of the preparation (Figure 8)
Summary
Gene silencing using synthetic oligonucleotides such as a small-interfering RNA (siRNA) or an antisense oligonucleotide (ASO) is a promising approach for suppressing the expression of pathogenic proteins in cells/tissues. Since these oligonucleotides are degraded by enzymes and eliminated from the systemic circulation by renal clearance, nano-sized drug delivery systems (DDS) are useful for protection from degradation and the control of their pharmacokinetics [1]. Drug Administration (FDA) and the European Medicines Agency (EMA) [3] Based on this success, the use of an LNP-type DDS promises to further contribute to the development of siRNA therapeutics/gene therapy
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