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