Special Issue "Nucleic Acid Architectures for Therapeutics, Diagnostics, Devices and Materials"

A special issue of Nanomaterials (ISSN 2079-4991).

Deadline for manuscript submissions: 15 June 2019

Special Issue Editor

Guest Editor
Dr. Kirill Afonin

Department of Chemistry, UNC Charlotte, Charlotte, NC, USA
Website | E-Mail
Interests: programmable RNA and DNA nanoassemblies for controlled immunoregulation; biosensing; drug delivery

Special Issue Information

Dear Colleagues,

Nucleic acids (RNA and DNA) and their chemical analogs have been utilized as building materials due to their biocompatibility and programmability. RNA, which naturally possesses a wide range of different functions, is now widely investigated for its role as a responsive biomaterial which dynamically reacts to changes in the surrounding environment. It is now evident that artificially designed self-assembling RNAs that can form programmable nanoparticles and supra-assemblies will play an increasingly important part in a diverse range of applications such as macromolecular therapies, drug delivery systems, biosensing, tissue engineering, programmable scaffolds for material organization, logic gates, and soft actuators, just to name a few.

We anticipate a very exciting issue composed of research highlights, short communications, research articles, and reviews that will bring together the leading scientists who are exploring a wide range of the fundamental properties of RNA nanoassemblies suitable for biomedical applications. Areas of interest include (but are not limited to) the following:

  • RNA-based nanoparticles for therapeutic applications
  • Programmable RNA-based biosensors
  • RNA-based logic gates
  • RNA-based supra-assemblies
  • Dynamic RNA nanoparticles: concepts, design, and characterization
  • In vivo delivery of novel RNA nanomaterials
  • Immunological properties of novel RNA nanomaterials
  • Interactions of RNA nanoparticles with other classes of biological molecules (proteins, lipids, etc.)
  • Quantitative Structure-Activity Relationships in RNA nanomaterials
Dr. Kirill Afonin
Guest Editor

Manuscript Submission Information

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Keywords

  • Self-assembly
  • Co-transcriptional assembly
  • RNA nanoparticles
  • DNA nanoparticles
  • Therapeutic Nucleic Acids (TNA), Aptamers
  • Nucleic Acids-based biosensors
  • in vivo delivery of TNA

Published Papers (10 papers)

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Research

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Open AccessArticle A Suite of Therapeutically-Inspired Nucleic Acid Logic Systems for Conditional Generation of Single-Stranded and Double-Stranded Oligonucleotides
Nanomaterials 2019, 9(4), 615; https://doi.org/10.3390/nano9040615
Received: 15 December 2018 / Revised: 15 March 2019 / Accepted: 25 March 2019 / Published: 15 April 2019
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Abstract
Several varieties of small nucleic acid constructs are able to modulate gene expression via one of a number of different pathways and mechanisms. These constructs can be synthesized, assembled and delivered to cells where they are able to impart regulatory functions, presenting a [...] Read more.
Several varieties of small nucleic acid constructs are able to modulate gene expression via one of a number of different pathways and mechanisms. These constructs can be synthesized, assembled and delivered to cells where they are able to impart regulatory functions, presenting a potential avenue for the development of nucleic acid-based therapeutics. However, distinguishing aberrant cells in need of therapeutic treatment and limiting the activity of deliverable nucleic acid constructs to these specific cells remains a challenge. Here, we designed and characterized a collection of nucleic acids systems able to generate and/or release sequence-specific oligonucleotide constructs in a conditional manner based on the presence or absence of specific RNA trigger molecules. The conditional function of these systems utilizes the implementation of AND and NOT Boolean logic elements, which could ultimately be used to restrict the release of functionally relevant nucleic acid constructs to specific cellular environments defined by the high or low expression of particular RNA biomarkers. Each system is generalizable and designed with future therapeutic development in mind. Every construct assembles through nuclease-resistant RNA/DNA hybrid duplex formation, removing the need for additional 2′-modifications, while none contain any sequence restrictions on what can define the diagnostic trigger sequence or the functional oligonucleotide output. Full article
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Open AccessFeature PaperArticle First Step Towards Larger DNA-Based Assemblies of Fluorescent Silver Nanoclusters: Template Design and Detailed Characterization of Optical Properties
Nanomaterials 2019, 9(4), 613; https://doi.org/10.3390/nano9040613
Received: 19 March 2019 / Revised: 7 April 2019 / Accepted: 12 April 2019 / Published: 13 April 2019
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Abstract
Besides being a passive carrier of genetic information, DNA can also serve as an architecture template for the synthesis of novel fluorescent nanomaterials that are arranged in a highly organized network of functional entities such as fluorescent silver nanoclusters (AgNCs). Only a few [...] Read more.
Besides being a passive carrier of genetic information, DNA can also serve as an architecture template for the synthesis of novel fluorescent nanomaterials that are arranged in a highly organized network of functional entities such as fluorescent silver nanoclusters (AgNCs). Only a few atoms in size, the properties of AgNCs can be tuned using a variety of templating DNA sequences, overhangs, and neighboring duplex regions. In this study, we explore the properties of AgNCs manufactured on a short DNA sequence—an individual element designed for a construction of a larger DNA-based functional assembly. The effects of close proximity of the double-stranded DNA, the directionality of templating single-stranded sequence, and conformational heterogeneity of the template are presented. We observe differences between designs containing the same AgNC templating sequence—twelve consecutive cytosines, (dC)12. AgNCs synthesized on a single “basic” templating element, (dC)12, emit in “red”. The addition of double-stranded DNA core, required for the larger assemblies, changes optical properties of the silver nanoclusters by adding a new population of clusters emitting in “green”. A new population of “blue” emitting clusters forms only when ssDNA templating sequence is placed on the 5′ end of the double-stranded core. We also compare properties of silver nanoclusters, which were incorporated into a dimeric structure—a first step towards a larger assembly. Full article
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Open AccessArticle Suicide Gene Therapy By Amphiphilic Copolymer Nanocarrier for Spinal Cord Tumor
Nanomaterials 2019, 9(4), 573; https://doi.org/10.3390/nano9040573
Received: 11 February 2019 / Revised: 30 March 2019 / Accepted: 30 March 2019 / Published: 8 April 2019
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Abstract
Spinal cord tumors (SCT) are uncommon neoplasms characterized by irregular growth of tissue inside the spinal cord that can result in non-mechanical back pain. Current treatments for SCT include surgery, radiation therapy, and chemotherapy, but these conventional therapies have many limitations. Suicide gene [...] Read more.
Spinal cord tumors (SCT) are uncommon neoplasms characterized by irregular growth of tissue inside the spinal cord that can result in non-mechanical back pain. Current treatments for SCT include surgery, radiation therapy, and chemotherapy, but these conventional therapies have many limitations. Suicide gene therapy using plasmid encoding herpes simplex virus-thymidine kinase (pHSV-TK) and ganciclovir (GCV) has been an alternative approach to overcome the limitations of current therapies. However, there is a need to develop a carrier that can deliver both pHSV-TK and GCV for improving therapeutic efficacy. Our group developed a cationic, amphiphilic copolymer, poly (lactide-co-glycolide) -graft-polyethylenimine (PgP), and demonstrated its efficacy as a drug and gene carrier in both cell culture studies and animal models. In this study, we evaluated PgP as a gene carrier and demonstrate that PgP can efficiently deliver reporter genes, pGFP in rat glioma (C6) cells in vitro, and pβ-gal in a rat T5 SCT model in vivo. We also show that PgP/pHSV-TK with GCV treatment showed significantly higher anticancer activity in C6 cells compared to PgP/pHSV-TK without GCV treatment. Finally, we demonstrate that PgP/pHSV-TK with GCV treatment increases the suicide effect and apoptosis of tumor cells and reduces tumor size in a rat T5 SCT model. Full article
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Open AccessArticle Out-of-Plane Aptamer Functionalization of RNA Three-Helix Tiles
Nanomaterials 2019, 9(4), 507; https://doi.org/10.3390/nano9040507
Received: 16 February 2019 / Revised: 23 March 2019 / Accepted: 27 March 2019 / Published: 2 April 2019
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Abstract
Co-transcriptionally folding RNA nanostructures have great potential as biomolecular scaffolds, which can be used to organize small molecules or proteins into spatially ordered assemblies. Here, we develop an RNA tile composed of three parallel RNA double helices, which can associate into small hexagonal [...] Read more.
Co-transcriptionally folding RNA nanostructures have great potential as biomolecular scaffolds, which can be used to organize small molecules or proteins into spatially ordered assemblies. Here, we develop an RNA tile composed of three parallel RNA double helices, which can associate into small hexagonal assemblies via kissing loop interactions between its two outer helices. The inner RNA helix is modified with an RNA motif found in the internal ribosome entry site (IRES) of the hepatitis C virus (HCV), which provides a 90° bend. This modification is used to functionalize the RNA structures with aptamers pointing perpendicularly away from the tile plane. We demonstrate modifications with the fluorogenic malachite green and Spinach aptamers as well with the protein-binding PP7 and streptavidin aptamers. The modified structures retain the ability to associate into larger assemblies, representing a step towards RNA hybrid nanostructures extending in three dimensions. Full article
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Open AccessArticle Structural and Functional Stability of DNA Nanopores in Biological Media
Nanomaterials 2019, 9(4), 490; https://doi.org/10.3390/nano9040490
Received: 12 March 2019 / Revised: 22 March 2019 / Accepted: 23 March 2019 / Published: 29 March 2019
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Abstract
DNA nanopores offer a unique nano-scale foothold at the membrane interface that can help advance the life sciences as biophysical research tools or gate-keepers for drug delivery. Biological applications require sufficient physiological stability and membrane activity for viable biological action. In this report, [...] Read more.
DNA nanopores offer a unique nano-scale foothold at the membrane interface that can help advance the life sciences as biophysical research tools or gate-keepers for drug delivery. Biological applications require sufficient physiological stability and membrane activity for viable biological action. In this report, we determine essential parameters for efficient nanopore folding and membrane binding in biocompatible cell media. The parameters are identified for an archetypal DNA nanopore composed of six interwoven strands carrying cholesterol lipid anchors. Using gel electrophoresis and fluorescence spectroscopy, the nanostructures are found to assemble efficiently in cell media, such as LB and DMEM, and remain structurally stable at physiological temperatures. Furthermore, the pores’ oligomerization state is monitored using fluorescence spectroscopy and confocal microscopy. The pores remain predominately water-soluble over 24 h in all buffer systems, and were able to bind to lipid vesicles after 24 h to confirm membrane activity. However, the addition of fetal bovine serum to DMEM causes a significant reduction in nanopore activity. Serum proteins complex rapidly to the pore, most likely via ionic interactions, to reduce the effective nanopore concentration in solution. Our findings outline crucial conditions for maintaining lipidated DNA nanodevices, structurally and functionally intact in cell media, and pave the way for biological studies in the future. Full article
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Open AccessArticle Optimization of the Split-Spinach Aptamer for Monitoring Nanoparticle Assembly Involving Multiple Contiguous RNAs
Nanomaterials 2019, 9(3), 378; https://doi.org/10.3390/nano9030378
Received: 14 February 2019 / Revised: 4 March 2019 / Accepted: 4 March 2019 / Published: 6 March 2019
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Abstract
The fact that structural RNA motifs can direct RNAs to fold and self-assemble into predictable pre-defined structures is an attractive quality and driving force for RNA’s use in nanotechnology. RNA’s recognized diversity concerning cellular and synthetically selected functionalities, however, help explain why it [...] Read more.
The fact that structural RNA motifs can direct RNAs to fold and self-assemble into predictable pre-defined structures is an attractive quality and driving force for RNA’s use in nanotechnology. RNA’s recognized diversity concerning cellular and synthetically selected functionalities, however, help explain why it continues to draw attention for new nano-applications. Herein, we report the modification of a bifurcated reporter system based on the previously documented Spinach aptamer/DFHBI fluorophore pair that affords the ability to confirm the assembly of contiguous RNA strands within the context of the previously reported multi-stranded RNA nanoring. Exploration of the sequence space associated with the base pairs flanking the aptamer core demonstrate that fluorescent feedback can be optimized to minimize the fluorescence associated with partially-assembled RNA nanorings. Finally, we demonstrate that the aptamer-integrated nanoring is capable of assembling directly from transcribed DNA in one pot. Full article
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Open AccessArticle Fluorogenic RNA Aptamers: A Nano-platform for Fabrication of Simple and Combinatorial Logic Gates
Nanomaterials 2018, 8(12), 984; https://doi.org/10.3390/nano8120984
Received: 25 October 2018 / Revised: 16 November 2018 / Accepted: 20 November 2018 / Published: 28 November 2018
Cited by 3 | PDF Full-text (2672 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
RNA aptamers that bind non-fluorescent dyes and activate their fluorescence are highly sensitive, nonperturbing, and convenient probes in the field of synthetic biology. These RNA molecules, referred to as light-up aptamers, operate as molecular nanoswitches that alter folding and fluorescence function in response [...] Read more.
RNA aptamers that bind non-fluorescent dyes and activate their fluorescence are highly sensitive, nonperturbing, and convenient probes in the field of synthetic biology. These RNA molecules, referred to as light-up aptamers, operate as molecular nanoswitches that alter folding and fluorescence function in response to ligand binding, which is important in biosensing and molecular computing. Herein, we demonstrate a conceptually new generation of smart RNA nano-devices based on malachite green (MG)-binding RNA aptamer, which fluorescence output controlled by addition of short DNA oligonucleotides inputs. Four types of RNA switches possessing AND, OR, NAND, and NOR Boolean logic functions were created in modular form, allowing MG dye binding affinity to be changed by altering 3D conformation of the RNA aptamer. It is essential to develop higher-level logic circuits for the production of multi-task nanodevices for data processing, typically requiring combinatorial logic gates. Therefore, we further designed and synthetized higher-level half adder logic circuit by “in parallel” integration of two logic gates XOR and AND within a single RNA nanoparticle. The design utilizes fluorescence emissions from two different RNA aptamers: MG-binding RNA aptamer (AND gate) and Broccoli RNA aptamer that binds DFHBI dye (XOR gate). All computationally designed RNA devices were synthesized and experimentally tested in vitro. The ability to design smart nanodevices based on RNA binding aptamers offers a new route to engineer “label-free” ligand-sensing regulatory circuits, nucleic acid detection systems, and gene control elements. Full article
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Review

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Open AccessReview Smart-Responsive Nucleic Acid Nanoparticles (NANPs) with the Potential to Modulate Immune Behavior
Nanomaterials 2019, 9(4), 611; https://doi.org/10.3390/nano9040611
Received: 14 March 2019 / Revised: 29 March 2019 / Accepted: 8 April 2019 / Published: 12 April 2019
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Abstract
Nucleic acids are programmable and biocompatible polymers that have beneficial uses in nanotechnology with broad applications in biosensing and therapeutics. In some cases, however, the development of the latter has been impeded by the unknown immunostimulatory properties of nucleic acid-based materials, as well [...] Read more.
Nucleic acids are programmable and biocompatible polymers that have beneficial uses in nanotechnology with broad applications in biosensing and therapeutics. In some cases, however, the development of the latter has been impeded by the unknown immunostimulatory properties of nucleic acid-based materials, as well as a lack of functional dynamicity due to stagnant structural design. Recent research advancements have explored these obstacles in tandem via the assembly of three-dimensional, planar, and fibrous cognate nucleic acid-based nanoparticles, called NANPs, for the conditional activation of embedded and otherwise quiescent functions. Furthermore, a library of the most representative NANPs was extensively analyzed in human peripheral blood mononuclear cells (PBMCs), and the links between the programmable architectural and physicochemical parameters of NANPs and their immunomodulatory properties have been established. This overview will cover the recent development of design principles that allow for fine-tuning of both the physicochemical and immunostimulatory properties of dynamic NANPs and discuss the potential impacts of these novel strategies. Full article
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Open AccessReview Intracellular Imaging with Genetically Encoded RNA-Based Molecular Sensors
Nanomaterials 2019, 9(2), 233; https://doi.org/10.3390/nano9020233
Received: 22 January 2019 / Revised: 5 February 2019 / Accepted: 5 February 2019 / Published: 8 February 2019
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Abstract
Genetically encodable sensors have been widely used in the detection of intracellular molecules ranging from metal ions and metabolites to nucleic acids and proteins. These biosensors are capable of monitoring in real-time the cellular levels, locations, and cell-to-cell variations of the target compounds [...] Read more.
Genetically encodable sensors have been widely used in the detection of intracellular molecules ranging from metal ions and metabolites to nucleic acids and proteins. These biosensors are capable of monitoring in real-time the cellular levels, locations, and cell-to-cell variations of the target compounds in living systems. Traditionally, the majority of these sensors have been developed based on fluorescent proteins. As an exciting alternative, genetically encoded RNA-based molecular sensors (GERMS) have emerged over the past few years for the intracellular imaging and detection of various biological targets. In view of their ability for the general detection of a wide range of target analytes, and the modular and simple design principle, GERMS are becoming a popular choice for intracellular analysis. In this review, we summarize different design principles of GERMS based on various RNA recognition modules, transducer modules, and reporting systems. Some recent advances in the application of GERMS for intracellular imaging are also discussed. With further improvement in biostability, sensitivity, and robustness, GERMS can potentially be widely used in cell biology and biotechnology. Full article
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Open AccessReview Vectors for Glioblastoma Gene Therapy: Viral & Non-Viral Delivery Strategies
Nanomaterials 2019, 9(1), 105; https://doi.org/10.3390/nano9010105
Received: 13 November 2018 / Revised: 21 December 2018 / Accepted: 3 January 2019 / Published: 16 January 2019
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Abstract
Glioblastoma multiforme is the most common and aggressive primary brain tumor. Even with aggressive treatment including surgical resection, radiation, and chemotherapy, patient outcomes remain poor, with five-year survival rates at only 10%. Barriers to treatment include inefficient drug delivery across the blood brain [...] Read more.
Glioblastoma multiforme is the most common and aggressive primary brain tumor. Even with aggressive treatment including surgical resection, radiation, and chemotherapy, patient outcomes remain poor, with five-year survival rates at only 10%. Barriers to treatment include inefficient drug delivery across the blood brain barrier and development of drug resistance. Because gliomas occur due to sequential acquisition of genetic alterations, gene therapy represents a promising alternative to overcome limitations of conventional therapy. Gene or nucleic acid carriers must be used to deliver these therapies successfully into tumor tissue and have been extensively studied. Viral vectors have been evaluated in clinical trials for glioblastoma gene therapy but have not achieved FDA approval due to issues with viral delivery, inefficient tumor penetration, and limited efficacy. Non-viral vectors have been explored for delivery of glioma gene therapy and have shown promise as gene vectors for glioma treatment in preclinical studies and a few non-polymeric vectors have entered clinical trials. In this review, delivery systems including viral, non-polymeric, and polymeric vectors that have been used in glioblastoma multiforme (GBM) gene therapy are discussed. Additionally, advances in glioblastoma gene therapy using viral and non-polymeric vectors in clinical trials and emerging polymeric vectors for glioma gene therapy are discussed. Full article
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