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WIREs Nanomed Nanobiotechnol
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Theranostic small interfering RNA nanoparticles in cancer precision nanomedicine

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Abstract Due to their ability to effectively downregulate the expression of target genes, small interfering RNA (siRNA) have emerged as promising candidates for precision medicine in cancer. Although some siRNA‐based treatments have advanced to clinical trials, challenges such as poor stability during circulation, and less than optimal pharmacokinetics and biodistribution of siRNA in vivo present barriers to the systemic delivery of siRNA. In recent years, theranostic nanomedicine integrating siRNA delivery has attracted significant attention for precision medicine. Theranostic nanomedicine takes advantage of the high capacity of nanoplatforms to ferry cargo with imaging and therapeutic capabilities. These theranostic nanoplatforms have the potential to play a major role in gene specific treatments. Here we have reviewed recent advances in the use of theranostic nanoplatforms to deliver siRNA, and discussed the opportunities as well as challenges associated with this exciting technology. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanomaterials and Implants
RNA interference pathways with small interfering RNA (siRNA) (left) and microRNAs (miRNA) (right). With siRNA, the cytosolic enzyme Dicer cleaves long dsRNAs into shorter siRNA fragments siRNAs, leaving two nucleotide 3′ overhangs and 5′ phosphate groups that are recognized by the Argonaute 2 (AGO2)‐RNAi‐induced silencing complex (RISC) enzyme complex. If the RNA loaded onto RISC has perfect sequence complementarity, AGO2 cleaves the passenger (sense) strand so that active RISC containing the guide (antisense) strand is produced. The siRNA guide strand recognizes target sites to direct mRNA cleavage (de Fougerolles, Vornlocher, Maraganore, & Lieberman, ). siRNA must be fully complementary to its target mRNA to result in RNAi. With microRNA, endogenously encoded long hairpin containing primary microRNA transcripts (pri‐miRNAs) are transcribed by RNA polymerase II (Pol II). These pri‐miRNAs are converted to precursor miRNAs (pre‐miRNAs) by the Drosha enzyme complex. Exportin 5 transports these precursors to the cytoplasm from the nucleus. In the cytoplasm, these precursors bind to the Dicer enzyme complex, which processes the pre‐miRNA for loading onto the AGO2 and the RISC complex. When this pre‐miRNA‐AGO2‐RISC complex has imperfect sequence complementarity, the passenger (sense) strand is unwound, leaving a mature miRNA bound to active RISC. Mature miRNA with the RISC can recognize and bind the target sites (typically in the 3’‐UTR) in the mRNA to inhibit translation. Binding between miRNA and target mRNA can also cause target mRNA degradation of mRNA, forming processing (P)‐bodies. miRNA is partially complementary to its target mRNA. As a result one miRNA strand can recognize an array of mRNAs and therefore have multiple targets
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Gold NPs and the color changes of these nanoparticles (NPs). (a) Gold nanorods, color varies with aspect ratio; (b) silica–gold core–shell NPs, color varies with shell thickness; (c) gold nanocages, color varies with galvanic displacement by gold. (Reprinted with permission from Dreaden, Alkilany, Huang, Murphy, and El‐Sayed (). Copyright 2012 Royal Society of Chemistry (Chemical Society Reviews))
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Structure of (a) liposome and (b) micelle. siRNA, small interfering RNA
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(a) Scheme of degradation of dextran nanoplex and delivery of COX‐2 small interfering RNA (siRNA). (b) Decrease of prostaglandin E2 (PGE2) concentration in medium following treatment of cancer cells with COX‐2 siRNA/dextran nanoplex. (c) in vivo Cy5.5 fluorescence imaging showed accumulation of the dextran nanoplex in tumors. (d) Downregulation of COX‐2 in tumors by COX‐2 siRNA/dextran nanoplex. (Reprinted with permission from Z. H. Chen, Krishnamachary, Penet, and Bhujwalla (). Copyright 2018 Ivyspring International Publisher (Theranostics))
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Structure of (a) chitosan, (b) hyaluronic acid, and (c) dextran
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(a) Structure of a prostate specific membrane antigen (PSMA) theranostic agent that carries a prodrug enzyme to convert 5‐fluorocytosine (5‐FC) to 5‐fluorouracil (5‐FU) that is detected by 19F MRS and siRNA to downregulate choline kinase (Chk) that results in a decrease of total choline detected by 1H MRSI. (b) Increased retention of the theranostic agent in a PSMA expressing tumor compared to a non‐PSMA expressing tumor. (c) Functional changes in tumor metabolism detected by 1H MRSI, and the formation of the cytotoxic drug 5‐FU from 5‐FC in the tumor detected by 19F MRS. Adapted with permission from (Z. Chen et al., )
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Structures of cationic polymers commonly used for siRNA nanomedicine
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Imaging modalities available for theranostic nanomedicine and their advantages and disadvantages
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Theranostic nanomedicine combines detection with therapy by incorporating elements of nanoscience, chemistry, medicine, pharmacy, molecular biology and imaging
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Diagnostic Tools > In Vitro Nanoparticle-Based Sensing
Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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