Virus-Encapsulated DNA Origami Nanostructures for Cellular Delivery

Mikkilä, Joona; Eskelinen, Antti-Pekka; Niemelä, Elina H.; Linko, Veikko; Frilander, Mikko J.; Törmä, Païvi; Kostiainen, Mauri A.

doi:10.1021/nl500677j

Cited by 278 publications

(288 citation statements)

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“…[39] Despite this progress, it has been observed that the transfection of DNA structures is generally low [40] and that these objects are prone to degradation in biological environment. [41] Nevertheless, there exist techniques to presumably enhance both stability and transfection rates of the DNA structures by utilizing different sophisticated protection and coating mechanisms, such as virus protein [42] or lipid membrane encapsulation. [43] It has also been shown that spermidine-stabilized structures could be efficiently transfected by electroporation.…”

Section: Doi: 101002/adhm201700692mentioning

confidence: 99%

Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility

Auvinen

Zhang

Nonappa

et al. 2017

Adv Healthcare Materials

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181

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DNA nanotechnology has taken a giant leap toward real-life applications during the recent years. [1,2] After the invention of DNA origami in 2006, [3] the whole research field has grown exponentially. [2,4] Today there are numerous ways to build discrete user-defined, accurate, and fully addressable DNA nanostructures, such as scaffolded 2D and 3D origami [3,5,6] with twists, curves, and bends, [7,8] Lego-like objects formed from molecular canvases, [9] and wireframe-based meshed constructions. [10][11][12] The computational tools [11][12][13] for designing such objects have emerged along with these techniques, and this progress has opened up new possibilities for the researchers to effortlessly build their own nanostructures for tailored uses. [14] Recently demonstrated applications based on customized DNA nanostructures include artificial ion channels, [15] optical (plasmonic and photonic) structures, [16,17] high-precision molecular positioning devices, [18] modifiable templates for arranging, e.g., proteins, [19][20][21] polymers, [22] and nanotubes, [23] as well as DNA-assisted techniques for creating arbitrarily shaped metal nanoparticles. [24][25][26] Fully addressable DNA nanostructures, especially DNA origami, possess huge potential to serve as inherently biocompatible and versatile molecular platforms. However, their use as delivery vehicles in therapeutics is compromised by their low stability and poor transfection rates. This study shows that DNA origami can be coated by precisely defined oneto-one protein-dendron conjugates to tackle the aforementioned issues. The dendron part of the conjugate serves as a cationic binding domain that attaches to the negatively charged DNA origami surface via electrostatic interactions. The protein is attached to dendron through cysteinemaleimide bond, making the modular approach highly versatile. This work demonstrates the coating using two different proteins: bovine serum albumin (BSA) and class II hydrophobin (HFBI). The results reveal that BSA-coating significantly improves the origami stability against endonucleases (DNase I) and enhances the transfection into human embryonic kidney (HEK293) cells. Importantly, it is observed that BSA-coating attenuates the activation of immune response in mouse primary splenocytes. Serum albumin is the most abundant protein in the blood with a long circulation half-life and has already found clinically approved applications in drug delivery. It is therefore envisioned that the proposed system can open up further opportunities to tune the properties of DNA nanostructures in biological environment, and enable their use in various delivery applications.

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Section: Doi: 101002/adhm201700692mentioning

confidence: 99%

Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility

Auvinen

Zhang

Nonappa

et al. 2017

Adv Healthcare Materials

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181

144

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“…Mikkilä et al [47] combined virus capsid proteins (CPs) of cowpea chlorotic mottle virus (CCMV) with rectangular DNA origami sheets, resulting in CP-origami complexes with different morphologies ( Figure 1F). The highly flexible DNA rectangle could adopt either a rolled-up or a completely encapsulated form depending on the amount of CPs mixed with DNA origamis.…”

Section: Towards Dna-based Drug Delivery Vehicles and Advanced Therapmentioning

confidence: 99%

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

“…(E) A smart logic-gated DNA origami nanorobot for targeting cells and subsequently displaying the molecular payload [43]. (F) Rectangular DNA origamis coated with virus capsid proteins (CPs) for efficient cellular delivery: the complexes can adopt different conformations depending on the added capsid protein concentration [47]. (G) A virus-inspired membrane-encapsulated spherical DNA origami vehicle for decreasing immune activation and enhancing pharmacokinetic bioavailability [48].…”

Section: Shape-complementarity-based Constructionmentioning

confidence: 99%

“…One of them is to improve the pharmacokinetic bioavailability of the DNA-based structures in vivo. DNA origami structures can survive in cellular milieu [22] and against nucleases [20], but the circulation times of the objects could be increased by adjusting their modular properties (see above) or by creating novel protecting strategies such as protein- [47] or lipid membrane coatings [48].Another challenge in creating DNA-based delivery vehicles and nanomachines is arguably the relatively expensive synthesis of the starting materials. However, since the entire research field is constantly growing and developing, it is likely that scaling up of the production and simultaneous knockdown of the price will take place rapidly [3,64].…”

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DNA Nanostructures as Smart Drug-Delivery Vehicles and Molecular Devices

Linko

Ora

Kostiainen

2015

Trends in Biotechnology

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228

166

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Emerging DNA nanotechnologyThe field of structural DNA nanotechnology started around 30 years ago when Ned Seeman performed pioneering research with DNA junctions and lattices [1]. To date, a cornucopia of different DNA nanostructures and shapes based on WatsonCrick basepairing [2] have been designed and demonstrated, and the whole research area has enjoyed a rapid progress especially during the past decade [3]. The key player in the fast development of DNA nanotechnology has been the invention of DNA origami in 2006 [4]. The DNA origami method is based on folding a long single-stranded "DNA scaffold strand" into a customized shape with a set of short synthetic staple strands. The robustness of the technique has made it widely accessible.Since then, the method has been generalized to 3D-fabrication [5][6][7][8][9][10], and it enables shapes with custom curvatures, twists and bends [11,12]. Very recently, techniques for modular scaffold-free fabrication [13,14], 3D meshing and wireframe-based approaches [15][16][17], as well as shape-complementarity-based construction [18] of DNA objects have been introduced. In addition, powerful computational tools for designing and analyzing DNA nanostructures have been developed [19][20][21], which appreciably help researchers to create their own DNA nanoarchitectures for any conceivable application. Table 1 lists and 2 describes the novel design strategies that can be used for fabricating diverse DNA origami nanostructures and other complex DNA-based shapes for various nanotechnological purposes.The platonic DNA nanostructures and DNA origamis are by all means remarkably impressive examples of precise engineering and constructing at the nanoscale. However, the attractiveness of the origami method lies in the fact that one can add any desired functionality to the tailored DNA shapes by assembling other biomolecules and molecular components to them with nanometer precision. Importantly, DNA is inherently biocompatible, and its stability can be further tuned by the optional functionalization [20,[22][23][24]. Aforementioned superior features can be eventually exploited in designing artificial DNA-based biomachinery, such as nucleic acid devices [25] and protein-DNA hybrid structures [26] for nanomedicine and biosensing. In this focused review, we discuss the recent progress of the nanomedical applications of self-assembled DNA systems; especially the drug delivery vehicles and nanomachines based on the DNA origami technique. Towards DNA-based drug delivery vehicles and advanced therapeuticsThe tremendous self-assembly properties of DNA can be exploited in creating various programmable shapes and larger assemblies for cellular delivery for e.g. cancer and enzyme replacement therapy. The very first DNA origami nano-objects proposed to work as molecular containers for drug delivery applications were single-layer origamis, which were further assembled into 3D shapes -a tetrahedron [5] or hollow cubes [6,7] (Fig. 1A). Since then, cellular uptake for various DNA structures (based o...

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