Cellular delivery of enzyme-loaded DNA origami

Ora, Ari; Järvihaavisto, Erika; Zhang, Hongbo; Auvinen, Henni; Santos, Hélder A.; Kostiainen, Mauri A.; Linko, Veikko

doi:10.1039/c6cc08197e

Cited by 69 publications

(53 citation statements)

References 51 publications

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“…[ 25–27 ] Therefore, DONs have been increasingly employed for developing novel drug delivery systems [ 28,29 ] due to their versatile designability, high solubility, and intrinsic biocompatibility. [ 30–37 ] Moreover, certain types of DONs have been proven to be readily rapidly internalized by mammalian cells despite their negatively charged surface property. [ 38 ]…”

Section: Introductionmentioning

confidence: 99%

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Guo

et al. 2020

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under the context that Brentuximab vedotin (Adcetris) for relapsed Hodgkin lymphoma [5,6] and T-DM1 (Kadcyla) for HER2 + metastatic breast cancer [7,8] received clinical approval from the Food and Drug Administration (FDA). The socalled "magic bullet," originally conceived by Paul Ehrlich, [9] are designed to combine the toxicity of small-molecule drugs with the targeting ability of antibodies to improve overall efficacy and therapeutic index. [10][11][12][13][14][15] Although conceptually straightforward, development of ADCs is encountered with several challenges including manageable toxicity, homogeneous conjugation and limited drug payload capacity. The balance between drug-to-antibody ratio (DAR) and targeting capability is mandatory for ADCs to reduce the attrition rate of drug candidates. Very high DAR ADCs may suffer decreased recognition to the target antigen. [16][17][18][19] Hence, it is highly desirable to develop ADCs with both high maximum tolerated doses and high selectivity. [20][21][22] Recently, the bloom of structural DNA nanotechnology [23,24] has demonstrated unprecedented precision on structural control, which enables predictable and programmable construction of complex nanostructures by exploiting intra-and inter-molecular Watson-Crick base-pairing. The programmability and addressability of DNA origami nanostructures (DONs) enable multiple desired functional moieties (such as therapeutic cargoes and tumor targeting ligands) with designer geometry and density. [25][26][27] Therefore, DONs have been increasingly employed for developing novel drug delivery systems [28,29] due to their versatile designability, high solubility, and intrinsic biocompatibility. [30][31][32][33][34][35][36][37] Moreover, certain types of DONs have been proven to be readily rapidly internalized by mammalian cells despite their negatively charged surface property. [38] We herein propose that DONs with certain framework [39] could serve as an ideal scaffold for ADCs analogues with exceptional control over targeting ligand density and drug loading contents for optimized antitumor efficacies and safety profile. [40] Specifically, we construct a new prostate cancer (PCa)specific drug delivery system by introducing different numbers of ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) to a designed six-helical-bundle DNA origami nanostructure (6HB DON). DUPA has been demonstrated to be a high-affinity inhibitor (K i ≈ 0.02 × 10 −9 -0.1 × 10 −9 m) for prostate-specific membrane antigen (PSMA). [41] We incorporate this Effective drug delivery systems that can systematically and selectively transport payloads to disease cells remain a challenge. Here, a targeting ligandmodified DNA origami nanostructure (DON) as an antibody-drug conjugate (ADC)-like carrier for targeted prostate cancer therapy is reported. Specifically, DON of six helical bundles is modified with a ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) against prostate-specific membrane antigen (PSMA), to serve as the antibody f...

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Section: Introductionmentioning

confidence: 99%

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Guo

et al. 2020

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“…[27][28][29][30] These examples cover logic-gated nanorobots for modulating cell signaling, [31] structures for delivering anticancer drugs [32][33][34] and for circumventing drug-resistance, [35,36] as well as carriers equipped with siRNA molecules, [37] CpGtriggers, [38] and functional enzymes. [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.…”

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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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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“…Just ten years after their introduction, DNA origami nanostructures are widely used in various fields of applied and fundamental research. Nowadays, DNA origami act as masks in molecular lithography, templates for nanoelectronic and plasmonic device fabrication, as delivery vehicles in molecular medicine, and substrates for single‐molecule experiments . Many of these applications rely on an intact and well‐defined shape as well as tailored mechanical properties of the DNA origami.…”

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confidence: 99%

Cation‐Induced Stabilization and Denaturation of DNA Origami Nanostructures in Urea and Guanidinium Chloride

Ramakrishnan

Krainer

Grundmeier

et al. 2017

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The stability of DNA origami nanostructures under various environmental conditions constitutes an important issue in numerous applications, including drug delivery, molecular sensing, and single-molecule biophysics. Here, the effect of Na and Mg concentrations on DNA origami stability is investigated in the presence of urea and guanidinium chloride (GdmCl), two strong denaturants commonly employed in protein folding studies. While increasing concentrations of both cations stabilize the DNA origami nanostructures against urea denaturation, they are found to promote DNA origami denaturation by GdmCl. These inverse behaviors are rationalized by a salting-out of Gdm to the hydrophobic DNA base stack. The effect of cation-induced DNA origami denaturation by GdmCl deserves consideration in the design of single-molecule studies and may potentially be exploited in future applications such as selective denaturation for purification purposes.

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Cellular delivery of enzyme-loaded DNA origami

Cited by 69 publications

References 51 publications

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

DNA Origami‐Enabled Engineering of Ligand–Drug Conjugates for Targeted Drug Delivery

Protein Coating of DNA Nanostructures for Enhanced Stability and Immunocompatibility

Cation‐Induced Stabilization and Denaturation of DNA Origami Nanostructures in Urea and Guanidinium Chloride

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