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WIREs Nanomed Nanobiotechnol
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Targeted siRNA delivery using aptamer‐siRNA chimeras and aptamer‐conjugated nanoparticles

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The sequence‐specific gene‐silencing ability of small interfering RNA (siRNA) has been exploited as a new therapeutic approach for the treatment of a variety of diseases. However, efficient and safe delivery of siRNA into target cells is still a challenge in the clinical development of siRNA‐based therapeutics. Recently, nucleic acid‐based aptamers that target cell surface proteins have emerged as a new class of targeting moieties due to their high specificity and avidity. To date, various aptamer‐mediated siRNA delivery systems have been developed to enhance the RNA interference (RNAi) efficacy of siRNA via targeted delivery. In this review, we summarize recent advances in developing aptamer‐mediated siRNA delivery systems for RNAi therapeutics, mainly aptamer–siRNA chimeras and aptamer‐functionalized nanocarriers incorporating siRNA, with a focus on their molecular designs and formulations. In addition, the challenges and engineering strategies of aptamer‐mediated siRNA delivery systems for clinical translation are discussed.

This article is categorized under:

  • Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures
  • Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Schematic illustration of the intracellular small interfering RNA (siRNA) delivery to a target cell and RNA interference (RNAi) machinery using aptamer–siRNA chimeras and aptamer‐conjugated, siRNA‐loaded nanocarriers. The aptamer–siRNA chimeras and aptamer‐conjugated, siRNA‐loaded nanocarriers bind to target cell receptors through the aptamer. The aptamer–siRNA chimeras and aptamer‐conjugated, siRNA‐loaded nanocarriers are internalized by the cells via endocytosis. After endosomal escape, the siRNA is recognized by RNAi machinery. The ribonuclease Dicer will bind to the siRNA part of the aptamer–siRNA chimeras and cut it off the aptamer. The siRNA are then incorporated into a RNA‐inducing silencing complex (RISC), which specifically degrades the target messenger RNA (mRNA) through complementary base pairing, followed by inhibition of its translation into target proteins
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Schematic illustration of aptamer‐functionalized AgNCs‐mediated cell type‐specific small interfering RNA (siRNA) delivery and tracking. Fluorescent AgNCs were first synthesized through the reduction of Ag+ by NaBH4 with biotin‐NC‐Sgc8c‐L5T as a template. Then Sgc8c aptamer‐functionalized AgNCs were coupled with biotinylated siRNA via a modular streptavidin bridge. Last, the formed complex was incubated with the target cells for specific siRNA delivery and tracking with the help of aptamer internalization and the Ag NCs fluorescent emission. (Reprinted with permission from Li et al. (). Copyright 2013 the Royal Society of Chemistry)
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Schematic representation of cationic nanoparticles for targeted delivery of small interfering RNA (siRNA)–aptamer chimeras. (a) Immobilization of preformed siRNA‐aptamer chimeras onto positively charged, poly(maleic anhydride‐alt‐1‐tetradecene (PAMT) and PEI‐coated QD nanoparticles (QD–PMAT–PEI). The aptamer block collapsed on the carrier results in reduced binding activity. (b) Two‐step immobilization of chimeras on a cationic nanoparticle surface. siRNA molecules with a thiol‐reactive terminal group are first adsorbed on the QD–PMAT–PEI surface to reduce the positive charge; subsequently aptamers with a single thiol group are brought in to form siRNA–aptamer chimeras on the nanoparticle surface. Compared with conventional one‐step adsorption of siRNA–aptamer chimeras onto nanoparticles with random orientations and conformations, two‐step immobilization of chimeras onto nanoparticles shows more efficient and targeted gene silencing due to retained conformation and high accessibility of the aptamers. (Reprinted with permission from Bagalkot and Gao (). Copyright 2011 American Chemical Society)
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Molecular structures of the oligoarginine‐functionalized, pH‐responsive methoxyl‐polyethylene glycol‐b‐poly(2‐(diisopropylamino) ethyl methacrylate‐co‐glycidyl methacrylate [Meo‐PEG‐b‐P(DPA‐co‐GMA‐Rn)] and prostate cancer‐specific polymer S,S‐2‐[3‐[5‐amino‐1‐carboxypentyl]ureido]pentanedioic acid (ACUPA)–PEG–b–PDPA and a schematic illustration of the multifunctional envelope‐type nanoparticles for in vivo prostate cancer‐specific small interfering RNA (siRNA) delivery. The two polymers can coassemble with siRNA to form stable nanoparticles with ACUPA targeting ligands encoded on the surface (a); siRNA‐loaded nanoparticles are systemically injected to mice (b, c); the siRNA‐loaded nanoparticles can extravasate from leaky tumor vasculature (d) and target the tumor tissue through the specific interaction between ACUPA and overexpressed PMSA on prostate cancer cells (e); After cellular uptake (f), the sharp pH‐responsive characteristics of the polymers induce fast disassembly of the nanoparticles, and the exposed membrane‐penetrating oligoarginine grafts lead to efficient endosomal escape (g), thus resulting in efficient gene silencing to inhibit tumor growth (h). (Reprinted with permission from Xu et al. (). Copyright 2017 American Chemical Society)
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(a) Schematic illustration of protein tags‐conjugated aptamer–small interfering RNA (siRNA) chimera. Chimera composed of an aptamer block targeting PSMA and a siRNA block targeting GFP forms a hair‐pin like structure. Protein tags were composed of a double‐stranded RNA‐binding domain (dsRBD) for siRNA docking and a pH‐dependent polyhistidine to disrupt endosomal membrane. The dsRBD domain has two double‐stranded RNA‐binding motifs (dsRBM1 and dsRBM2) for cooperative and dsRNA‐specific binding. Protein tags with varying lengths of polyhistidines, as shown in the domain architectures, are engineered to achieve balanced endosomal escape and RNA‐binding functionalities. (b) Confocal micrographs of GFP expressing C4‐2 cells treated with various samples. The panels from left to right are differential interference contrast, fluorescence, and merged images. In contrast to the no treatment group, chimera complexed with dsRBD‐His18 shows significantly higher GFP knockdown. (Adapted from Liu and Gao (). Copyright 2013 Springer Nature Limited)
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(a) Schematic illustration of the developed Holliday junction incorporated with four aptamer–small interfering RNA (siRNA) conjugates (Holliday–Apt–siRNA). (b) Schematic illustration of the intracellular uptake of the aptamer–siRNA conjugate (Apt–siRNA) and the Holliday–Apt–siRNA by aptamer‐mediated endocytosis. Endosomal escape of Holliday–Apt–siRNA was significantly enhanced by preincubation with endosome breaking reagents (ER) such as cationic PEI. (c) Gene‐silencing efficiency of Holliday–Apt–siRNA in two MUC1‐positive cell lines stably expressing GFP (KB‐GFP cells and MCF‐7‐GFP cells). siRNA concentration is 10 nM. NC indicates a negative control. LF indicates lipofectamine (*p < .05; ns = not significant). (Reprinted with permission from Jeong, Jeong, et al. (). Copyright 2017 Elsevier)
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Schematic showing the cell‐specific silencing strategy mediated by PEI nanocomplex fabricated with aptamer and small interfering RNA (siRNA). PEI nanoparticle is formed using sodium citrate as charge stabilizer, followed by the addition of siRNA and epithelial cell adhesion molecule (EpCAM) aptamer to form the PEI–aptamer–siRNA complex. This complex are guided by the aptamer, binds to the EpCAM positive cells, and delivers the siRNA in the cytoplasm, resulting in target gene silencing and inhibited cell proliferation. (Adapted from Subramanian, Kanwar, Athalya, et al. (). Copyright 2015 BioMed Central)
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(a) Schematic of the anti‐HIV‐1 gp120 aptamer–small interfering RNA (siRNA) chimeras. The anti‐gp120 aptamer binds to gp120, and the 27‐mer Dicer substrate RNA duplex targets a common exon of the HIV‐1 tat/rev (Zhou et al., ). (b) Schematic of the anti‐HIV‐1 gp120 aptamer‐sticky bridge‐siRNA conjugates. Either antisense or sense strand of the 27‐mer Dicer substrate RNA duplex and aptamers were attached to complementary “sticky” sequences (Zhou et al., ). (Adapted from Zhou and Rossi (). Copyright 2010 BioMed Central Ltd.)
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(a) Schematic illustration of intracellular processes of multivalent Dox–aptamer–small interfering RNA (siRNA) (Dox–Apt–siRNA) and its antiapoptotic gene silencing combined with Dox‐mediated cytotoxicity. (b) Activity of caspase‐3/7 in multidrug‐resistant (MDR) MCF‐7 cells treated with free Dox, Dox–siRNA, Dox–Apt–siRNA, and multivalent Dox–Apt–siRNA for 2 days. Ns: No significant difference between values; *p < .01 between values. (c) Viability of MDR MCF‐7 cells treated with free Dox, Dox–siRNA, Dox–Apt–siRNA, and multivalent Dox–Apt–siRNA for 4 days. Ns: No significant difference versus untreated control cells; **p < .05 versus untreated control cells. (Adapted from Jeong, Lee, et al. (). Copyright 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Schematic illustrations for the (a) preparation of multivalent comb‐type aptamer–small interfering RNA (siRNA) conjugates and (b) their cellular uptake into mucin 1 (MUC1)‐overexpressing cancer cells. Antisense siRNA strands were linearly connected via thiol‐maleimide coupling using the chemical crosslinker to produce multimerized antisense siRNA strands. MUC1 aptamer‐sense strands of siRNAs were complementary hybridized to multimeric and dimeric antisense for the fabrication of comb‐type aptamer–siRNA conjugates and dimeric aptamer–siRNA conjugates. (Reprinted with permission from Yoo et al. (). Copyright 2014 The Royal Society of Chemistry)
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Schematic presentation of the typical SELEX procedure. A library of RNA or DNA oligonucleotides comprising constant terminal regions for primer annealing and a randomized central region (typically 20–50 nt) is prepared. The library is incubated with the selected target molecule. DNA or RNA molecules that bind to the target are prospective aptamers for that target. After unbound sequences are removed, the bound sequences are separated from the target and purified. The bound sequences are then amplified by polymerase chain reaction (PCR), generating a more specific sequence library. This iterative process is performed for several rounds in order to enrich for sequences that specifically bind to the target molecule. (Adapted from Kruspe and Giangrande (). Copyright 2017 MDPI)
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures

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