Insight into the siRNA transmembrane delivery—From cholesterol conjugating to tagging

Abstract

Small interfering RNA (siRNA), combining the features of unprecedented potency, target‐specificity, and the unique sequence‐based disease‐intervention model, has received immense considerations over the past decades in the academia and pharmaceutical industry. siRNA fits the criteria of being drug‐likely enough to meet with the therapeutic purpose, but its clinical translation has been impeded for a long time by the poor efficiency of in vivo delivery. To reach the cytosol where the RNA interference (RNAi) takes place, siRNA delivery faces a serial of systemic and cellular barriers, especially the endosomal sequestration that would prevent the majority of siRNA from cytosol entry. Transmembrane delivery of siRNA represents a new avenue for efficient delivery by bypassing the endosomal pathway. This rationale is bolstered by the high efficiency of viral entry by membrane fusion, but rarely pursued by artificial siRNA delivery systems. Here, this article provides an opinion of transmembrane delivery by hydrophobic modulation of siRNA. We give a brief introduction of the current siRNA delivery modes, including the hydrophobic cholesterol siRNA conjugates. The cholesterol tagging technology is design on the rationale of hydrophobic siRNAs approach, but hydrophobic modulation throughout the whole siRNA backbone for efficient membrane fusion and transmembrane delivery. The challenge and potential of this technology for preclinical development are also discussed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Lipid‐Based Structures Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures

Hemocyte siRNA uptake is increased by 5′ cholesterol-TEG addition in Biomphalaria glabrata, snail vector of schistosome

“…In Biomphalaria snail, since the first study reporting the proof of concept for siRNAmediated gene silencing (Jiang, Loker & Zhang, 2006), only one has been reported comparing the effect of siRNA and long dsRNA soaked juvenile snails on the silencing of the Cathepsin B gene using a cationic polymer vector (Knight et al, 2011). In the present study, we initially focused on the optimization of hemocyte siRNA uptake by conjugating with cholesterol as it was known to be a driving force to enhance cell-penetrating nucleic acid sequences (Zheng & Tai, 2020). Interestingly, the delivery of Chol-siRNAs into HeLa cells has been shown to be very rapid and saturate in less than one hour (Gilleron et al, 2015).…”

Polymeric Drug Delivery Systems Bearing Cholesterol Moieties: A Review

“…By using cholesterol-containing systems, endocytosis or fusion of siRNA [100] or pDNA [134] is possible. It is worth noting that there are promising studies on the transmembrane transport of cholesterol-modified siRNA [176].…”

Delivery of Oligonucleotides: Efficiency with Lipid Conjugation and Clinical Outcome

“…It was believed that conjugated ON was sequestered during late endosome, which coiled the term endosomal entrapment [50]. Hence, chemical enhancers were used to damage vesicles along the endosomal system to promote escape [51,52]. Additionally, the delivery scope of cholesterol conjugated oligonucleotide was very limited to hepatic cells and to some extend pancreatic cells [53].…”