Drug delivery systems based on nucleic acid nanostructures

Vries, Jan Willem de; Zhang, Feng; Herrmann, Andreas

doi:10.1016/j.jconrel.2013.05.022

Cited by 77 publications

(55 citation statements)

References 172 publications

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“…8 The platform is modular and can be easily adjusted to each new RNA target or transformed to accommodate additional functions including modifications to enable targeted sensor delivery to cancer cells, or drug load for catalytic drug release in the presence of specific RNA targets, the concepts developed earlier. 16 We, therefore, hypothesize that complex multifunctional sensors like MDMR1 reported here will replace traditional probes in the analysis of nucleic acids.…”

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confidence: 93%

DNA nanotechnology for nucleic acid analysis: multifunctional molecular DNA machine for RNA detection

et al. 2016

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The Nobel prize in chemistry in 2016 was awarded for 'the design and synthesis of molecular machines'. Here we designed and assembled a molecular machine for the detection of specific RNA molecules. An association of several DNA strands, named multifunctional DNA machine for RNA analysis (MDMR1), was designed to (i) unwind RNA with the help of RNA-binding arms, (ii) selectively recognize a targeted RNA fragment, (iii) attract a signal-producing substrate and (iv) amplify the fluorescent signal by catalysis. MDMR1 enabled detection of 16S rRNA at concentrations ~24 times lower than that by a traditional deoxyribozyme probe.Hybridization probes have been used for the detection of specific DNA and RNA sequences for the last 55 years. 1a Common challenges of hybridization probes include insufficient sensitivity and selectivity. 1 Detection of specific RNA molecules is particularly challenging due to the stable secondary structures that inhibit or even prevent their interactions with hybridization probes. 2 For example, some molecular beacon probes, fluorophore-and quencher-labelled DNA stem-loop structures, 3 were previously shown to fail in detecting folded RNA and DNA molecules. 4 Probes based on nucleic acid analogues, e.g. peptide nucleic acids and locked nucleic acids, are required to tightly bind and unwind structured RNAs. 5 Here we took advantage of recent developments of DNA nanotechnology 6 to design a multifunctional platform that enables (i) unfolding of a specific RNA analyte, (ii) specific recognition of a targeted fragment, (iii) enhanced delivery of a signal-producing substrate to a target-activated catalytic sensor, and (iv) signal amplification by catalysis. We named the platform 'multifunctional DNA machine 7 for RNA analysis of the 1st generation' (MDMR1).MDMR1 was designed based on binary deoxyribozyme (BiDZ) probe, 8 in which two unmodified DNA strands, DZ a and DZ b , hybridize to the abutting positions of a complementary DNA or RNA analyte to form the catalytic core of an RNA-cleaving deoxyribozyme (Fig. 1A). 9 The active core cleaves a fluorophore-and a quencher-labelled F_sub strand, which results in a production of a fluorescent signal. For BiDZ, as the signal † Electronic supplementary information (ESI) available: Detailed experimental procedure and the structure of MDMR1; data used for calculations of LODs, as well as kinetics of MDRRA1 that lacks RNA-binding arm or Hook strand. See DOI: 10.1039/c6cc06889hCorrespondence to: D. M. Kolpashchikov. 1,3b However, the LOD of BiDZ sensors is compromised when long and highly folded RNA is to be analysed. In this case, the access of the BiDZ probe to the targeted analyte fragment is limited resulting in ~10-25 fold decrease in LOD in comparison to an unstructured analyte. 8h,l We therefore seek to equip the BiDZ probe with the RNAunwinding function. We reasoned that the addition of an RNA-unwinding function to the BiDZ probe will help to facilitate its access to the targeted fragment and achieve lower LODs. Furthermore, deoxyriboz...

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confidence: 93%

DNA nanotechnology for nucleic acid analysis: multifunctional molecular DNA machine for RNA detection

et al. 2016

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“…As DNA is a natural molecule, it can be degraded by endogenous pathways and consequently toxicity is deemed unlikely. 23,24 From simple structures such as polyhedrons 25,26,27 up to very complex designs using the DNA origami approach, 28,29,30 various different shapes have been established from which only a few have been tested for siRNA delivery. Examples include a DNA tetrahedron or a DNA nanotube conjugated to siRNA and folate, which could be delivered to folate receptor–bearing cells.…”

Section: Introductionmentioning

confidence: 99%

DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization

Heissig

Klein

Hadwiger³

et al. 2016

Molecular Therapy - Nucleic Acids

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siRNA and microRNA are promising therapeutic agents, which are engaged in a natural mechanism called RNA interference that modulates gene expression posttranscriptionally. For intracellular delivery of such nucleic acid triggers, we use sequence-defined cationic polymers manufactured through solid phase chemistry. They consist of an oligoethanamino amide core for siRNA complexation and optional domains for nanoparticle shielding and cell targeting. Due to the small size of siRNA, electrostatic complexes with polycations are less stable, and consequently intracellular delivery is less efficient. Here we use DNA oligomers as adaptors to increase size and charge of cargo siRNA, resulting in increased polyplex stability, which in turn boosts transfection efficiency. Extending a single siRNA with a 181-nucleotide DNA adaptor is sufficient to provide maximum gene silencing aided by cationic polymers. Interestingly, this simple strategy was far more effective than merging defined numbers (4–10) of siRNA units into one DNA scaffolded construct. For DNA attachment, the 3′ end of the siRNA passenger strand was beneficial over the 5′ end. The impact of the attachment site however was resolved by introducing bioreducible disulfides at the connection point. We also show that DNA adaptors provide the opportunity to readily link additional functional domains to siRNA. Exemplified by the covalent conjugation of the endosomolytic influenza peptide INF-7 to siRNA via a DNA backbone strand and complexing this construct with a targeting polymer, we could form a highly functional polyethylene glycol–shielded polyplex to downregulate a luciferase gene in folate receptor–positive cells.

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“…Self-assembled nanostructures derived from nucleic acids (DNA and RNA) are increasingly being employed as agents for delivery of functional ONs and show significant promise for overcoming the current barriers to ON delivery [88-90]. In comparison to other methods, DNA nanotechnology is a highly efficient and controllable strategy for creating structures of defined shape and size through rational design and construction [91].…”

Section: Carrier-associated Conjugatesmentioning

confidence: 99%

Bioconjugates for targeted delivery of therapeutic oligonucleotides

Xin

Laing

2015

Advanced Drug Delivery Reviews

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Bioconjugates have been used to deliver therapeutic oligonucleotides to their pharmacological targets in diseased cells. Molecular-scale conjugates can be prepared by directly linking targeting ligands with oligonucleotides and the resultant conjugates can selectively bind to cell surface receptors in target cells in diseased tissues. Besides targeted delivery, additional functionality can be incorporated in the conjugates by utilization of carrier molecules, and these larger conjugates are called carrier-associated conjugates. Both molecular and carrier-associated conjugates have achieved initial successes in clinical trials for treating liver diseases; therefore, currently the greater challenge is to deliver oligonucleotides to extrahepatic tissues such as tumors. This review will provide an update on the application of oligonucleotide conjugates for targeted delivery during the last decade. By identifying key elements for successful delivery, it is suggested that oligonucleotide conjugates with intermediate size, cell targeting ability, and endosomal release functionality are superior systems to advance oligonucleotides to achieve their full therapeutic potentials.

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Drug delivery systems based on nucleic acid nanostructures

Cited by 77 publications

References 172 publications

DNA nanotechnology for nucleic acid analysis: multifunctional molecular DNA machine for RNA detection

DNA nanotechnology for nucleic acid analysis: multifunctional molecular DNA machine for RNA detection

DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization

Bioconjugates for targeted delivery of therapeutic oligonucleotides

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