Abstract
The efficient and precise delivery of siRNA to target cells is critical to successful gene therapy. While novel nanomaterials enhance delivery efficiency, it still remains challenging for precise gene delivery to overcome nonspecific adsorption and off-target effect. Here we design a dual lock-and-key system to perform cell-subtype-specific recognition and siRNA delivery. The siRNA is self-assembled in an oligonucleotide nano vehicle that is modified with a hairpin structure to act as both the ‘smart key’ and the delivery carrier. The auto-cleavable hairpin structure can be activated on site at target cell membrane by reacting with two aptamers as ‘dual locks’ sequentially, which leads to cell-subtype discrimination and precise siRNA delivery for high efficient gene silencing. The success of this strategy demonstrates the precise delivery of siRNA to specific target cells by controlling multiple parameters, thus paving the way for application of RNAi in accurate diagnosis and intervention.
Highlights
The efficient and precise delivery of small interference RNA (siRNA) to target cells is critical to successful gene therapy
The ‘locked’ hairpin structure of sgc8c is opened by hybridizing with the cleaved single-strand oligonucleotide in siRNA-oligonucleotide nano vehicle (ONV) subsequently to mediate the precise delivery of siRNA into specific target cells
The ‘dual lock-and-key’-controlled delivery approach demonstrated effective Vascular endothelial growth factor (VEGF) gene silencing in target cells by inhibiting the VEGF messenger RNA (mRNA) expression down to 47.1% and VEGF protein production down to 49.1%48–50, which was comparable with Lipo2000 mediation transfection, TKO mediation transfection and 2nd-siRNA-ONV
Summary
Kewei Ren1,*, Ying Liu1,*, Jie Wu1, Yue Zhang[1], Jing Zhu[1], Min Yang2 & Huangxian Ju1. The auto-cleavable hairpin structure can be activated on site at target cell membrane by reacting with two aptamers as ‘dual locks’ sequentially, which leads to cell-subtype discrimination and precise siRNA delivery for high efficient gene silencing. The success of this strategy demonstrates the precise delivery of siRNA to specific target cells by controlling multiple parameters, paving the way for application of RNAi in accurate diagnosis and intervention. In comparison with ‘single-parameter’-controlled siRNA delivery, the ‘dual lock-and-key’-controlled siRNA delivery system activates two recognition elements on site at target cell membrane just before the delivery process, affords substantial improvement for delivery specificity and avoids offtarget toxicities, which is of great importance to the application of RNAi in precise diagnosis and treatment
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