Cell‐Penetrating and Neurotargeting Dendritic siRNA Nanostructures

Brunner, Korbinian; Harder, Johannes; Halbach, Tobias S.; Willibald, Julian; Spada, Fabio; Gnerlich, Felix; Sparrer, Konstantin M. J.; Beil, Andreas; Möckl, Leonhard; Bräuchle, Christoph; Conzelmann, Karl‐Klaus; Carell, Thomas

doi:10.1002/anie.201409803

Cited by 49 publications

(32 citation statements)

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“…Another strategy to stabilize siRNA polyplexes is the conversion of single siRNA molecules into larger polyanions by hybridization, chemical ligation, click‐chemistry, and coformulation with pDNA, or other polyanions. Our group recently used DNA oligomers as adaptors to increase the size and charge of siRNA to form more stable polyplexes and thus boost transfection efficacies .…”

Section: Nucleic Acid Binding—the Polyplex Formation Processmentioning

confidence: 99%

How to Tackle the Challenge of siRNA Delivery with Sequence‐Defined Oligoamino Amides

Reinhard

Wagner

2016

Macromolecular Bioscience

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RNA interference (RNAi) as a mechanism of gene regulation provides exciting opportunities for medical applications. Synthetic small interfering RNA (siRNA) triggers the knockdown of complementary mRNA sequences in a catalytic fashion and has to be delivered into the cytosol of the targeted cells. The design of adequate carrier systems to overcome multiple extracellular and intracellular roadblocks within the delivery process has utmost importance. Cationic polymers form polyplexes through electrostatic interaction with negatively charged nucleic acids and present a promising class of carriers. Issues of polycations regarding toxicity, heterogeneity, and polydispersity can be overcome by solid-phase-assisted synthesis of sequence-defined cationic oligomers. These medium-sized highly versatile nucleic acid carriers display low cytotoxicity and can be modified and tailored in multiple ways to meet specific requirements of nucleic acid binding, polyplex size, shielding, targeting, and intracellular release of the cargo. In this way, sequence-defined cationic oligomers can mimic the dynamic and bioresponsive behavior of viruses.

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Section: Nucleic Acid Binding—the Polyplex Formation Processmentioning

confidence: 99%

How to Tackle the Challenge of siRNA Delivery with Sequence‐Defined Oligoamino Amides

Reinhard

Wagner

2016

Macromolecular Bioscience

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“…A strategy commonly pursued is the formation of larger defined structures containing multiple siRNA units. 18,19,20 DNA oligomers can be used as a framework to merge several siRNA units into one construct. 21,22 DNA is especially suitable for this purpose as it is simply accessible and a huge variety of structures can be assembled by Watson Crick base pairing.…”

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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“…The reaction mixture was heated to 90 1C for 30 min followed by the addition of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate 19 (900 mg, 2.4 mmol) in 10 ml acetonitrile. The UV/vis absorption spectra were corrected for the solvent.…”

Section: Methodsmentioning

confidence: 99%