View PDF VersionPrevious ArticleNext Article
 
DOI: 10.1039/D0AN02160A (Minireview) Analyst, 2021, 146, 1807-1819

DNA origami: an outstanding platform for functions in nanophotonics and cancer therapy

Lizhi Dai† a, Peng Liu† a, Xiaoxue Hu a, Xiaozhi Zhao *b, Guoqiang Shao *c and Ye Tian *a
aCollege of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, 210093, China. E-mail: ytian@nju.edu.cn
bAffiliated Drum Tower Hospital, School of Medicine, Institute of Urology, Nanjing University, Nanjing, 210008, China. E-mail: zhaoxz@nju.edu.cn
cDepartment of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. E-mail: guoqiangshao@163.com

Received 31st October 2020 , Accepted 1st February 2021

First published on 3rd February 2021

Abstract

Due to the proposal and evolution of the DNA origami technique over the past decade, DNA molecules have been utilized as building blocks for the precise construction of nanoscale architectures. Benefiting from the superior programmability of DNA molecules, the sequence-dependent recognition mechanism and robust complementation among DNA strands make it possible to customize almost arbitrary structures. Such an assembly strategy bypasses some of the limits of conventional fabrication methods; the fabrication accuracy and complexity of the target product are unprecedentedly promoted as well. Furthermore, due to the spatial addressability of the final products, nanostructures assembled through the DNA origami technique can also serve as a versatile platform for the spatial positioning of functional elements, represented by colloidal nanoparticles (NPs). The subsequent fabrication of heterogeneous functional nanoarchitectures is realized via modifying colloidal NPs with DNA strands and manipulating them to anchor into DNA origami templates. This has given rise to investigations of their novel properties in nanophotonics and therapeutic effects towards some diseases. In this review, we survey the crucial progress in the development of DNA origami design, assembly and structural analysis and summarize available applications in nanophotonics and cancer therapy based on the object-dressed DNA origami complex. Moreover, we elucidate the development of this field and discuss the potential directions of this kind of application-oriented nanomanufacturing.

1. Introduction

A molecular self-assembly process is generally initiated and accomplished on a minute scale and relies on noncovalent molecular interactions, such as hydrophobic bonds which maintain the stereo structures of some proteins, hydrogen bonds and van der Waals interactions.1–3 Compared with stable covalent interactions, these kinds of molecular interactions are normally weak; thus, corresponding products must be supported for adequate fabrication accuracy during the assembly process to guarantee the integrity of final products, particularly those with complex structures. Technically, the emergence and booming evolution of DNA technology has revealed unparalleled potential in bottom-up fabrication and has been considered the most appropriate solution to meet challenges.4,5 As revealed from the groundbreaking discovery in 1953, the molecular conformation of the DNA double helix is governed through the inherent interaction between Watson–Crick base pairs. As a consequence, the hybridization process of a DNA duplex can be precisely realized according to the specific recognition of nucleotide bases. This mechanism has propelled researchers to utilize DNA molecules to construct elaborate nanostructures with the help of an extensively automatic and user-defined DNA synthetic technique. The corresponding efforts are reflected in the use of the DNA origami technique, which constructs delicate nanostructures by employing DNA strands as building blocks and whose products can serve as the universal templates for guiding functional units to compose into more sophisticated structures; these contributions are extremely difficult to implement using normal methods.6,7 In this review, we provide an overview about how we artificially design DNA origami structures and then establish multifarious patterns of functional NPs through DNA origami assembly. Some remarkable properties and applications afforded by the DNA origami technique will be introduced according to their functionalities in nanophotonics and cancer therapy; discussions on future possible opportunities in this interdisciplinary community will also be presented in the following sections.

2. Fundamentals, design and assembly of DNA origami

The seminal research for this innovative method for bottom-up assembly was pioneered by Prof. Paul Rothemund in 2006 (Fig. 1).8 He used an unprecedented approach to assemble two-dimensional nanoarchitectures with a long, annular single stranded DNA (ssDNA) and numerous short oligonucleotides. Some relatively simple shapes, such as a smiling face, triangle, rectangle, and five-pointed star, were created and the associated procedures involved in the assembly process can be subdivided into the following four steps: (1) converting the target shape into a geometrical model which has the same approximate profile as the target shape with the DNA double helices inside the shape idealized as parallel cylinders. It is noteworthy that the lengths of the DNA duplexes were intentionally controlled to fit the morphologies of the target shapes and each helix was constrained to be an integer number of turns in length. (2) Incorporating a series of periodic arrays of crossovers into the model. Crossovers function indicatively to guide DNA strands to switch to an adjacent helix from their original direction at the designated positions. DNA strands extend along the transformed directions after running across the crossover points. (3) Filling the shape with a naturally circular, single-stranded DNA derived from the bacteriophage M13mp18. The long genomic DNA consists of 7249 nucleotides (nt) and is functionally equivalent to a scaffold in constructional engineering. The specific operation of this filling procedure is carried out via folding the scaffold DNA back and forth to fit the cylinders in the model. In the previous step, crossovers were assigned every 1.5 helical turns (16 base pairs) along alternating sides of a helix to guarantee that the scaffold strand can continuously route through each adjacent helix and comprise one of the two strands in every helix. Then a set of short oligonucleotides termed ‘staple strands’ are introduced to provide the complements to the long scaffold strand at pathways and periodic crossovers; thus, the scaffold strand can be immobilized at determined positions by antiparallel staple strands and manifold prescribed patterns can be precisely created. (4) Finally, prepared strands are mixed based on the given stoichiometry. After undergoing a slow thermal annealing procedure, the designed structures are ultimately replicated from the design with high accuracy. Complying with these design considerations, explorations have sprung up based on this novel technique. Fan and co-workers reported an advance in the construction of asymmetrical DNA origami structures by creating a nanoscale DNA structure of an analogic map of China with a spatial resolution of 6 nm.9 Shih et al. extended the DNA origami technique to build successive custom three-dimensional (3D) configurations.10,11 In addition to assembling DNA origami nanostructures (DONs) approximating six disparate shapes, they also combined controllable twist and curvature elements into the design process to construct more intricate structures and enrich the variety of assembled products. Gothelf and Kjems et al. synthesized a dynamic object with box-shaped geometry which possessed stimuli-response behavior in the presence of external DNA strands.12 Afterwards, a smaller reconfigurable DNA origami box was built with approximate 1/7 of the volume of the first DNA box. The smaller box has a repeated opening and closing mechanism under the excitation of light.13 Yan et al. constructed a ribbon-like Möbius strip with only one side and demonstrated that the obtained DNA Möbius strip can be reconfigured through the strand displacement reaction to create topological objects such as supercoiled ring and catenane structures.14 They proceeded to present a strategy to rationally design and engineer a series of nanostructures with intricate curvatures, including concentric rings, spherical shells, ellipsoidal shells and nanoflasks, in 2D and 3D spaces.15 Furthermore, they adopted four-arm junctions as basic structural units to construct a variety of complex gridiron-like wireframe architectures.16 Högberg et al. established a method to build arbitrary polygonal wireframe structures which are more complicated than those designed by preceding strategies to obtain complex structures with open conformation via automatic design pathways.17 Similar efforts were made by the Bathe group to create different types of nearly arbitrary DNA architectures through a target shape-oriented strategy.18 Creatively, DNA nanostructures were also obtained by combining several basic DNA origami components through hydrogen bonding or the stacking interaction of DNA duplexes; the obtained DNA objects possessed a larger size than conventional DONs.19,20
image file: d0an02160a-f1.tif
Fig. 1 (a) Design principle of DNA origami technique.8 Images reproduced from ref. 8 with permission. Copyright 2006 Springer Nature. (b) Representative 2-dimensional DONs.8 Images reproduced from ref. 8 with permission. Copyright 2006 Springer Nature. (c) Monolith, square nut and railed bridge DNA origami shapes obtained by honeycomb design method.10 Images reproduced from ref. 10 with permission. Copyright 2009 Springer Nature. (d) Different DNA bundles with controllable twists and curvatures.11 Images reproduced from ref. 11 with permission. Copyright 2009 AAAS. (e) Top row: Molecular model of nanoscale DNA origami box and surface and cut-open views of 3D reconstructed density maps computed from single-particle cryo-EM (electron microscope) images. Bottom row: Schematic illustration of programmed opening-closing mechanism of DNA origami box.12 Images reproduced from ref. 12 with permission. Copyright 2009 Springer Nature. (f) Stereo DNA nanostructures with complex and subtle curvatures.15 Images reproduced from ref. 15 with permission. Copyright 2011 AAAS. (g) A series of complicated DONs obtained by an automated design method.17 Images reproduced from ref. 17 with permission. Copyright 2015 Springer Nature. (h) Polyhedral DNA origami frames obtained by connecting tunable DNA tripods.19 Images reproduced from ref. 19 with permission. Copyright 2014 AAAS. (i) Diverse high-order DNA objects composed of multilayer DNA origami hexagons via shape-complementary interactions under a set of different magnesium concentrations.20 Images reproduced from ref. 20 with permission. Copyright 2015 AAAS.

The DNA origami technique exploited a robust methodology to engineer nanoscale structures which relies on its outstanding customization and spatial addressability and corresponding research is always ongoing.21–30 Paradoxically, although the sequence design and stoichiometry of DNA strands are normally non-specific, nanostructures yielded by the DNA origami technique are larger and more complex than previously attempted. Consequently, DNA origami brings a profound reform to the field of bottom-up fabrication and facilitates applications including the detection of optical signals and chemical markers, exploration of interfacial properties of soft materials, drug delivery and so on. The advances in this field have imbued the DNA origami technique with attributes which connect this method with the fields of condensed matter physics, analytical chemistry, and chemicobiology and make these fields flourish based on the mutual interdisciplinary rewards.

3. Nanoarchitectures templated by DNA origami

The DNA origami technique has been consistently associated with the field of precision manufacturing during its evolutionary process. When the tough issue of organizing minute materials into fairly complicated structures was raised, researchers gradually realized the task could accomplished by means of DNA origami. Due to the programmability of the design process, the sequential specificity of DNA strands and the spatial addressability of target structures, the DNA origami technique has revealed distinct superiority in manipulating the arrangement of nanomaterials with the ultimate aim of building infinite superstructures. Nanomaterials such as metallic NPs, semi-conductive NPs and some proteins can be handled readily with the aid of this feasible template (Fig. 2).31
image file: d0an02160a-f2.tif
Fig. 2 Representative examples of DON-templated architectures. Nanoparticles are organized into manifold 1D, 2D and 3D configurations (a–h) under the guidance of DON templates.33,36–41,48 Images reproduced from ref. 33 with permission. Copyright 2010 American Chemical Society. Images reproduced from ref. 36 with permission. Copyright 2011 Wiley. Images reproduced from ref. 37 with permission. Copyright 2014 Springer Nature. Images reproduced from ref. 38 with permission. Copyright 2015 Wiley. Images reproduced from ref. 39 with permission. Copyright 2015 Springer Nature. Images reproduced from ref. 40 with permission. Copyright 2016 Springer Nature. Images reproduced from ref. 41 with permission. Copyright 2016 American Chemical Society. Images reproduced from ref. 48 with permission. Copyright 2020 Wiley.

Construction of nanoarchitectures relies on the building of DNA origami motifs and their corresponding assemblies; chemical modification of any guest objects is requisite as well. Selected nano-objects are normally easy to externally decorate with nucleic acids as a corona and can hybridize with DNA strands protruding from the origami structure; fabrication proceeds after the initiation of the anchoring process.

Yan and colleagues pioneered a reliable strategy to assemble gold nanoparticle (AuNP)-DNA conjugates with rectangular origami structures.32 Then, Yan et al. reported an innovative method to organize multiple AuNPs into a linear pattern with the guidance of discrete DNA origami structures.33 It has been verified that the number and orientation of AuNPs could be precisely regulated with the assistance of the DNA origami from this work. Contemporaneously, Yan, Liu and co-workers successfully fabricated silver nanoparticles (AgNPs) into stable AgNP multimers with varying interparticle distances through a similar method,34 which expanded the diversity of colloidal NPs applicable to this strategy and inspired later research.35 Subsequently, they used 3D DNA origami nanocages to encapsulate AuNPs inside as well as anchor them on surface to prepare stereoscopic core–shell complexes.36 Subsequently, assembly of colloidal NPs has been sustainably carried forward by researchers to realize more advanced organization with superior precision and complexity. Liedl et al. reported the strategy of utilizing DNA origami scaffolds and metal NPs to construct a number of planet–satellite-type architectures with tunable stoichiometry and controllable sizes.37 Another kind of novel structure with greater size, composed of AuNPs and triangular DNA origami, was fabricated by Fan et al.38 Furthermore, Gang's group reported their progress in the fabrication of stereo anisotropic nanoclusters and sophisticated planar geometries. They created a highly symmetric octahedral DNA origami frame and generated multiple anisotropic structures through the frame structure and attached AuNPs.39 After that, they further showcased a universally available method to program manifold 2-dimensional (2D) AuNP patterns using square-shaped DNA modules.40 Linear chains, zig-zag chains, homogeneous 2D arrays and even nanoscale analogues of Leonardo da Vinci's Vitruvian Man were fabricated via this approach. Wang and Ke also imaginatively contributed to this field.41,42 They embedded gold nanorods (AuNRs) inside predesigned DNA nano-clamps to realize surficial addressability: AuNPs were subsequently anchored onto the nano-clamps to deploy a configuration of AuNRs–AuNPs conjugates. Similar attempts were also carried out on semi-conductive colloidal NPs, represented by quantum dots (QDs).37,43,44 Ding and Fan et al. reported the creative construction of metallic and inorganic patterns with nano-scale precision by in situ generation on DNA origami templates, which provided an unconventional process for the fabrication of nano-architectures.45–47 Inspired by previous accomplishments, our group recently proposed a general approach to transform isotropic AuNPs to AuNPs-DNA patches with the help of octahedral DNA shells, which are capable of serving as a versatile platform to organize a family of coordination polymer analogues.48 Alternatively, precise assembly of colloidal NPs can be limited around a robust interface.49 Corresponding research was performed on the involvement of micro-sized magnetic beads (MBs); AuNP multimers could be readily synthesized as the feedback of this surface-restrained method. DNA origami templates have imparted considerable programmability to the manipulation of the arrangements of colloidal objects participating in assembly while simultaneously modulating the mutual interaction and placement between colloidal components and DNA templates to tailor certain properties of the nanoarchitectures prior to practical application in fields including nanophotonics, cellular uptake and subsequent disease treatment.

4. Applications in nanophotonics

DNA origami templates have facilitated the construction of well-defined colloidal superstructures and thus enabled a number of photoinduced plasmonic phenomena induced by the interaction of light and specifically arranged metallic NPs. The key requirement of plasmonic properties is that the spacing of the NPs be arranged with the appropriate proximity to realize the excitation of chirality, fluorescence and surface enhanced Raman scattering (SERS). The aforementioned contributions have gradually demonstrated the reliable methodology of DNA origami mediated colloidal NPs placement; the method permits the customization of compactly organized NPs with an accuracy down to a few nanometers, allowing the explorations of optical response and nanodevices based on DNA-NPs conjugates to flourish. In this section, we present a retrospective of the variety of impressive progress and explorations in DNA origami-assisted nanophotonic application, subdivided into species with various surface plasmonic properties, including circular dichroism and SERS.

Circular dichroism (CD)

As a reliable spectroscopic methodology to detect and study the manifold molecules which possess natural or synthetic chirality, circular dichroism is commonly used to monitor the difference between the extinction of left-handed (LH) and right-handed (RH) polarized light after being absorbed by molecules and materials. The prerequisite for chiral molecular configurations, so-called enantiomers, is that their mirror images cannot be superimposed, which uncovers the feasibility to artificially build chiral objects under the absolute control of DNA origami/NPs hybrid structures due to the incredible ability of DNA origami to arrange NPs (Fig. 3).
image file: d0an02160a-f3.tif
Fig. 3 (a) Left- and right-handed (LH and RH) nanohelices constructed by immobilizing AuNPs on DNA origami bundles.50 Images reproduced from ref. 50 with permission. Copyright 2012 Springer Nature. (b) Automatically transforming AuNPs-dressed 2D DNA origami into 3D chiral plasmonic nanostructures.51 Images reproduced from ref. 51 with permission. Copyright 2011 American Chemical Society. (c) LH and RH 3D plasmonic toroidal metamolecules formed by 24 AuNPs and DNA origami rings.53 Images reproduced from ref. 53 with permission. Copyright 2016 American Chemical Society. (d) RH AuNRs helices assembled by integrating AuNRs with 2D DNA origami templates.55 Images reproduced from ref. 55 with permission. Copyright 2014 American Chemical Society. (e) Reconfigurable 3D plasmonic meta-structures arranged by DNA origami templates.56 Images reproduced from ref. 56 with permission. Copyright 2014 Springer Nature. (f) Plasmonic nanorod walker organized by perpendicularly grafting AuNRs on layered DNA origami template.57 Images reproduced from ref. 57 with permission. Copyright 2015 Springer Nature. (g) AuNRs chiral plasmonic superstructure with stair helix construction templated by DNA origami monomers.58 Images reproduced from ref. 58 with permission. Copyright 2018 American Chemical Society.

A landmark attempt towards a DNA origami-mediated chiral structure was performed by Liedl and co-workers.50 They organized 10 nm AuNPs into two different staircase configurations by anchoring the AuNPs on rigid DNA origami 24-helix bundles along the LH and RH helical forms. The obtained plasmonic structures exhibited defined circular dichroism and optical rotatory dispersion effects at visible wavelengths, thus demonstrating that the chiral morphology and optical response of NPs architectures could be rationally modulated via the introduction of DNA origami templates. Furthermore, Ding et al. presented an alternative method for constructing 3D plasmonic chiral structures by binding AuNPs at specific sites on the surfaces of geometry-transformable 2D DNA origami templates.51 AuNPs can be automatically arranged in a helical fashion by rolling the origami templates and a corresponding excited circular dichroism response can be detected. They next fabricated a three-dimensional asymmetric tetramer with four nominally identical AuNPs on a planar DNA origami template and obtained a pronounced chiral signature aroused by resonant coupling between the AuNPs, which was in agreement with prior theoretical predictions.52 Going a step further, Liu, Ke and Ding et al. developed a hierarchical assembly system to organize twenty-four AuNPs into toroidal metamolecular patterns and obtained a tailored chiroptical response in the visible spectral range.53 Wang et al. provided the first case of discrete 3D AuNR dimers with controlled spatial orientation.54 This arrangement of AuNRs was realized by installing two AuNRs on opposite sides of a rectangular bifacial DNA origami template; the modified optical properties can be characterized after tuning the docking position of anisotropic AuNRs. They further employed AuNRs for the construction of helical superstructures with manipulatable inter-rod spacing, inter-rod angle and deterministic handedness.55 The two types of optically reversed AuNR helices were assembled by artificially stacking and rotating AuNRs along the normal direction under the guidance of 2D origami templates and displayed predictable chiroptical activities during circular dichroism spectra measurements. Comparably, Liu and collaborators exploited a reconfigurable active plasmonic nanosystem comprised of two crossed AuNRs hosted by a DNA origami template.56 Distinct conformational states of the AuNRs can be obtained by regulating the relative angles of two bundles in the DNA templates; such configurational changes were transduced in situ into circular dichroism changes. They subsequently demonstrated another active plasmonic system with a AuNR executing directional and progressive walking on two and three-dimensional DNA origami templates.57 The walking states of this type of machine can be translated into an optical response depending on the dynamic coupling of the AuNRs within the walker systems. Yan et al. created a gold nanorod 3D chiral plasmonic superstructure with a stair helix configuration templated by DNA origami and the optical response can be dynamically controlled.58 The representative explorations mentioned above and a number of similar works59–68 have given rise to the development of DNA-mediated optical response and brought insight to these physical–chemical interdisciplines.

SERS

The concept of SERS was developed from the physical phenomenon of the remarkable enhancement of the inelastic Raman scattering signal by the absorption of target molecules onto roughened metal surface.69 To date, as a departure from conventional Raman spectroscopy, SERS analysis is generally acknowledged to be an applicable method for analyzing trace amounts of markers in the material sciences, biological detections, and pharmaceuticals, given its superiorities of high sensitivity and low detection limits. More importantly, a boosted Raman signal could be detected when placing target molecules in plasmonic hot spots surrounded by localized electromagnetic fields, in spite of the existing shortcoming of Raman substrates during signal detection. The crucial hot spots lie in the narrow gaps between metal surfaces and provide the opportunity for DNA origami to showcase its salient capability to organize metallic objects into plasmonic superstructures with predefined spacing and geometries (Fig. 4).
image file: d0an02160a-f4.tif
Fig. 4 (a) Plasmonic AuNPs dimeric structures assembled on a DNA origami template with rhodamine 6G adsorbed inside.71 Images reproduced from ref. 71 with permission. Copyright 2014 Springer Nature. (b) Nanoantenna built by linking two gold nanoparticles with a three-layered DNA origami block to realize a plasmonic “hot spot”.72 Images reproduced from ref. 72 with permission. Copyright 2014 American Chemical Society. (c) Dimeric AuNPs nanostructures with controllable gap size for SERS detection.73 Images reproduced from ref. 73 with permission. Copyright 2016 American Chemical Society. (d) AuNPs tetramers arranged by rectangular origami for SERS enhancement.74 Images reproduced from ref. 74 with permission. Copyright 2014 American Chemical Society. (e) Dimeric nanostar structures assembled through DNA origami template for single-molecule SERS measurement.75 Images reproduced from ref. 75 with permission. Copyright 2017 American Chemical Society. (f) Bowtie nanostructures comprised of two Au prisms on DNA origami template for SERS measurement.76 Images reproduced from ref. 76 with permission. Copyright 2018 Wiley.

Building on the first realized case of DNA origami mediated SERS signal detection,70 Keyser et al. employed DNA origami platforms to arrange two individual AuNPs into a dimer with a gap of around 3.3 nm,71 and SERS was adopted for the detection of a small number of dye molecules and ssDNA oligonucleotides to corroborate the local field enhancements. Similarly, Lohmüller et al. built a nanoantenna through the introduction of two AuNPs.72 Templated by three-layered DNA origami blocks, discrete AuNPs were assembled into couples with an interparticle distance of 6 nm, SERS measurements were taken, and pronounced enhancement of the Raman signal was obtained after embedding Raman-active molecules into the origami blocks. They then further reduced the separation distance of the AuNPs to the range of 1 to 2 nm by utilizing an optothermal-induced shrinking process of the DNA origami template;73 consequently, the detection sensitivity was propelled towards single-molecule resolution. Finkelstein et al. reported plasmonic structures composed of four AuNPs positioned at the corners of rectangular origami templates.74 Significant enhancement of the Raman signal of 4-aminobenzenethiol molecules was detected in hot spots within four adjacent AuNPs after solution-based metal deposition. Moreover, Sen et al. expanded the geometric shapes of the metallic objects to non-spherical Au nanostars to induce higher SERS efficiency, which was attributed to the electric field enhancement of the sharp tips of the Au nanostars.75 By immobilizing Au nanostars on 2D DNA origami templates and inserting Texas red (TR) dye in the conjunction region with the dimeric Au nanostar structures, an enhanced electromagnetic field was excited and quantified by single-molecule SERS spectroscopy. Ding et al. provided an approach utilizing Au nanoprisms for the organization of Au bowtie nanostructures resorted by the template feature of DNA origami.76 A single Raman probe was precisely positioned at the gap region of the bowtie structure and repeatable local field enhancement of several orders of magnitude was achieved. Furthermore, Fan et al. anchored several large AuNPs on assembled triangular DNA origami templates to build metamolecules with Fano resonances; the obtained superstructures can precisely localize single dye molecules and excite quantifiable SERS responses.77

5. Applications in cancer therapy

Human health has been an eternal theme and pursuit throughout the development of human society. However, it has been increasingly threatened by a variety of diseases, especially cancers. Despite the field of cancer therapy seeing the exploitation of hundreds of chemotherapeutic drugs in the past decades, the corresponding feedbacks have not all been regarded as completely therapeutic. Since the discovery of enhanced permeability and retention (EPR) effects in 1986, this unique phenomenon has been repeatedly verified to be subsistent in the microenvironment of solid tumors, related to their anatomical and pathophysiological differences from normal tissues.78–82 This significant finding with respect to oncology provided a great impetus to the development and studies of macromolecular anticancer drugs, also termed nanomedicines. Many nanostructured materials have been validated as effective in targeting tumor tissues based on the EPR effect.83–86 Given the structural-customizability of the DNA origami technique, DONs have been increasingly utilized as vehicles to deliver cancer drugs into tumor tissues. Apart from the controllable stereo configuration, the high cellular uptake efficiency, the modifiable property of DNA strands and the intrinsic biocompatibility of DONs endowed by the endogenous character of nucleic acids have spawned many investigations of the in vivo transport behaviour of DONs.87

Normally, two aspects have been primarily focused on by researchers during the drug delivery process of DONs. First, the types of loads attached on the DNA origami are determined by the types of cancer, the site and the mechanism of action of the drugs. Second, the efficient and stable delivery of the origami and accurate identification by cancer cells for pesticide effect are important. In the following sections, we will summarize the efforts made by researchers to solve these problems.

Payloads on DONs

Small-molecule drugs. Small-molecule drug doxorubicin (Dox) is a chemotherapeutic drug extensively applied clinically to treat cancers and is also commonly adopted as a model drug in experimental mechanism studies for cancer therapy. Through intercalation into DNA base pairs, Dox can be facilely combined into DONs. Variform DONs can serve as carriers and shells to encapsulate drugs and deliver them to target sites (Fig. 5). Högberg et al.88 studied the encapsulation efficiency and the release kinetics of the drug by tuning the number of twists in DONs. Compared with naked Dox molecules, DONs have revealed outstanding platform properties for drug internalization to destroy breast cancer cells. Ding et al. conducted a series of studies on Dox-containing DONs systems. As they reported in 2012, an increased cellular internalization effectiveness of Dox was realized when employing DONs as drug delivery vehicles, dramatically enhancing the cell-killing activity against not only the regular human breast cancer MCF-7 cell line but also doxorubicin-resistant MCF-7 cells.89 They also proved that DNA nanostructured vectors have the potential to circumvent Dox resistance by facilitating the efficient accumulation of drugs in cells. Next, they adopted triangular DONs to deliver Dox and tested them in vivo and in vitro.90 The results showed that the Dox-grafted DONs exhibited prominent antitumor efficacy and low systemic toxicity in nude mice bearing orthotopic breast tumors.
image file: d0an02160a-f5.tif
Fig. 5 (a) Dox-loaded DONs for cancer therapy.88 Images reproduced from ref. 88 with permission. Copyright 2012 American Chemical Society. (b) DONs for CpG delivery and immunostimulatory effects.92 Images reproduced from ref. 92 with permission. Copyright 2011 American Chemical Society. (c) A DNA nanorobot which can respond to a molecular trigger for thrombin delivery.95 Images reproduced from ref. 95 with permission. Copyright 2018 Springer Nature. (d) DONs for AuNRs delivery to realize OAI process and photothermal therapy.98 Images reproduced from ref. 98 with permission. Copyright 2016 Wiley.
Nucleic acids. Gene therapy currently appeals to researchers in the field of cancer therapy. It employs exogenous nucleic acid strands (e.g. short interfering RNA (siRNA) and cytosine-phosphate-guanine (CpG)) as medicine to execute corresponding functions.91 However, the lack of robust delivery systems in vivo made it difficult to guarantee efficiency and safety during the delivery process and has limited its clinical application. Through rational design, DONs can be modified with these kinds of genetic medicines anchored on the surface or encapsulated inside to realize secure delivery. Unmethylated CpG sequences of DNA can be identified by Toll-like receptor 9 (TLR9), thus inducing immunostimulatory effects. Liedl et al.92 synthesized CpG-decorated DONs to motivate immune response. The result indicated the outstanding delivery properties of nontoxic DON platforms carrying CpG oligonucleotides inside. Moreover, Shin et al. connected siRNA that targets anti-apoptotic protein B-cell lymphoma 2 (Bcl2) to a number of different DNA bricks.93 This study suggested that DNA bricks enable therapeutic siRNA to be delivered efficiently and are a promising clinical prospect.
Proteins. In 2019, Ding et al.94 provided an exemplary case of carrying proteins on DONs. The experiment was performed by integrating cytotoxic protein ribonuclease (RNase) A molecules and cancer cell-targeting aptamers into rectangular DNA origami nanosheets; the data showed an obvious antitumor effect. Furthermore, to reveal the vulnerability of the protein during transport, Ding and Zhao et al.95 constructed an autonomous DNA robot to deliver thrombin according to a pre-designed program. The thrombin can be exposed with the help of nucleolin-targeting aptamer under the protection of DNA robots and then effectively activates coagulation in the tumor region and induces intravascular thrombosis.
Light-triggered materials. Light-triggered materials, photosensitizers and AuNRs are often used in photodynamic therapy (PDT)96 and photothermal therapy (PTT) for cancer treatment. They have revealed definite advantages, including high tumor destruction selectivity, a noninvasive nature, low side effects, and extremely low drug resistance.

In 2016, Liang et al.97 created a dual-functional DONs platform with imaging and PDT functions. In their study, the photosensitizer 3,6-bis[2-(1-methylpyridinium)ethynyl]-9-pentylcarbazole diiodide (BMEPC) was attached to DONs. The photo-bleaching of BMEPC within cells was effectively reduced and the intramolecular rotation of BMEPC was seemingly restricted so that the fluorescence emission and radical production strengthened during excitation. Simultaneously, Tian et al. designed an optoacoustic imaging (OAI) agent by anchoring AuNRs onto DONs.98 The system served as a specific probe and efficient contrast agent during the OAI process by combining the advantages of AuNRs and DONs. In this way, the imaging quality was improved while the dose was decreased. Meanwhile, AuNRs had an obvious response to NIR irradiation. Taking advantage of this phenomenon, they successfully inhibited tumor regrowth.

Combination of multiple therapeutic components. To achieve better treatment effect, researchers often use two or more drugs on the same nanocarrier. This strategy is termed combination therapy and has received attention from researchers over the past years. To solve multidrug resistance in the clinical treatment of cancer, Ding and co-workers set up a versatile DONs platform to use RNA interference and Dox to combat a multidrug-resistant tumor (MCF-7R) in vitro and in vivo.99 Using the same strategy, they designed a DNA nanostructure-based co-delivery system.100 In this system, linear tumor therapeutic gene (p53) and Dox were integrated to realize inhibition of the multidrug resistant tumor (MCF-7R). Recently, Chu et al. constructed a multifunctional DONs platform to deliver Dox and two different antisense oligonucleotides (ASOs), Bcl2 and P-glycoprotein (P-gp).101 In this investigation, an MUC1 sequence was fixed on the surface of DONs to enhance the targeting effect; the effect of cancer therapy conspicuously increased in conjunction with Dox, ASOs and aptamer. The aforementioned works demonstrated that DONs are a preeminent platform for drug delivery.

Enhancement of the stability and uptake efficiency of DONs

Morphology and uptake efficiency. Besides the payloads attached to DONs for the delivery of anti-tumor drugs, researchers focused on how to improve the stability of the DONs platform and enhance the effectiveness of treatment in a tumor area. Despite DONs ability to be synthesized into almost arbitrary configurations due to the remarkable programmability during the design process, exploring the types of DONs suitable for cell uptake in vivo and in vitro is an essential problem (Fig. 6).
image file: d0an02160a-f6.tif
Fig. 6 (a) Effect of size and shape of DONs on internalization efficiency.103 Images reproduced from ref. 103 with permission. Copyright 2018 American Chemical Society. (b) Higher uptake efficiency shown for DONs with a ligand.106 Images reproduced from ref. 106 with permission. Copyright 2020 Wiley. (c) Oligolysine-based coating approach for DONs to realize effective protection for in vivo applications.112 Images reproduced from ref. 112 with permission. Copyright 2017 Springer Nature. (d) DONs can alleviate acute kidney injury based on preferential renal uptake.119 Images reproduced from ref. 119 with permission. Copyright 2018 Springer Nature.

In 2018, to investigate the relationship between the size and shape of DONs and the internalization efficiency for cells, four DONs with different topologies were fabricated by Ke and co-workers; a small rod, large rod, small tetrahedron and large tetrahedron and three kinds of cells were used in this investigation.102 In their results, they found an interesting phenomenon: larger DONs are more easily absorbed by cells. They speculated that this tendency can be explained by the stronger interactions between large constructions and receptors. They also found that scavenger receptors play an important role to get DONs into cells. For different types of cells, there are significant differences when using the same kind of DONs, which is consistent with the conclusion in another study by Shih and co-workers.103 They designed 11 distinct DONs with diverse sizes ranging from 50–400 nm and examined the internalization efficiency in three different cell lines: human umbilical vein endothelial (HUVE) cells, bone-marrow-derived dendritic cells (BMDCs), and human embryonic kidney (HEK293) cells. They came to the conclusion that, in addition to the type of cells determining internalization efficiency, compact DONs ranging from 50 nm to 80 nm with a low aspect ratio performed better than other DONs when entering all three kinds of cells. Xu et al. explored the effect of DONs in transdermal drug delivery (TDD).104 In this study, 8 kinds of origami, including 3 tetrahedrons, 2 cylindrical rods, 2 rectangles and 1 triangle, with sizes ranging from 20 nm to 200 nm, were manufactured to examine topical penetration and drug carrier capability. They came to a similar conclusion as Shih. Many works more or less address this problem.90,93 Through these studies, we can obtain a rough understanding of how size and shape impact internalization efficiency.

Aptamer and uptake efficiency. In 2017, Ding et al. fabricated a multifunctional platform to restrain multidrug resistant MCF-7 cells.105 In their scheme, Dox, AuNRs and tumor-specific aptamer MUC-1 were integrated together into one triangular DNA origami platform. In the presence of the aptamer, this multifunctional platform was effectively taken up by cancer cells. They successfully proved the aptamer sequence is an excellent cancer-targeting ligand. Other aptamers, such as 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA)106 and the nucleolin aptamer C2NP107 have been applied as well. Kjems et al. inserted the transport protein transferrin (TF) into a planar DON.108 They demonstrated that DONs with TF promoted cell uptake and, as the number of transferrin molecules fixed on the origami surface changed, the internalization efficiency increased accordingly.
Methods to improve stability. In addition to the uptake efficiencies of different DONs, enhancement of the stability of DONs in physiological fluids and blood circulation is a classic research direction. Although Perrault et al. proved that DONs are resistant, to a certain degree, to degradation by nucleases compared to double-stranded DNA,109 low concentrations of cations in physiological fluids and nucleases are still predominant barriers for DONs serving as carriers. Crosslinking and external coatings are two promising methods to enhance the stability of DONs. Sugiyama et al. used 8-methoxypsoralen to realize photo-cross-linking.110 Manetto et al. used a common click chemistry reaction method to crosslink two DNA strands.111 In 2017, Shih et al. coated DONs with positively charged oligolysine or oligolysine-PEG and checked the stability in vivo and in vitro.112 The results showed DONs coated with oligolysine had great resistance to low salt but only modest protection from nuclease degradation, while DONs coated with oligolysine-PEG preformed excellently against degradation by nuclease (up to 400 fold). A moderate enhancement in circulation and biodistribution was also shown. Next, they utilized glutaraldehyde to crosslink PEGylated oligolysine coated in DONs.113 By this means, DONs with cross-linked oligolysine coats revealed an up to 250-fold increase of stability in protection from nuclease degradation. The Kostiainen group employed cowpea chlorotic mottle virus capsid proteins to encapsulate DONs.114 In this way, not only the stability increased but also, owing to the screening of electrostatic repulsion, the internalization efficiency was improved. In 2017, they tried a new strategy to coat DONs with protein.115 Here, the positively charged dendron part of the conjugate attached to the negatively charged DONs by electrostatic interactions while the protein is fixed in the dendron through the cysteinemaleimide bond. In this study, two different proteins, bovine serum albumin (BSA) and class II hydrophobin (HFBI), were used as coating layers. A series of tests indicated that the encapsulation approach improved the stability against endonucleases, enhanced transfection efficiency, and, more importantly, subdued the immune response. In addition to the above materials, peptoids116 and lipid bilayers,117 among others, have also been applied to coat DONs.

Apart from drug delivery for cancer therapy, DNA-based nanocarriers have been applied for tuberculosis treatment.118 It is worth mentioning that Cai et al. found that DONs showed great promise in the alleviation of acute kidney injury (AKI) and other renal diseases.119 They made three different DONs (rectangle, triangle and tube) and investigated the biodistribution of the different DONs in mice using PET imaging. Significantly, all three DONs exhibited preferential kidney accumulation compared to the control group. Based on this phenomenon, a rapid therapeutic response was demonstrated in AKI mice and new candidates emerged for the treatment of kidney diseases.

6. Conclusion

In this review, we summarize representative advances in the applications of DNA origami mediated nanophotonics and cancer therapy based on the evolution of the DNA origami technique. Indeed, the remarkable programmability and addressability shown by the DNA origami technique during the self-assembly process enables it to be an ideal tool to construct various complex structures and further tailor nano-objects into prescribed arrangements, feasibly for use as nanodevices in corresponding electric and biological systems. However, a number of remaining challenges still limit the utilization of DNA origami structures in practical applications. For instance, the stabilization and adaptability of DNA origami structures under diverse physical conditions, especially certain unfavourable conditions, must be addressed and might be overcome by efficient protection strategies. Moreover, progress in synthesizing DNA origami components and corresponding assemblies above the micrometer scale are rarely reported; this bottleneck should be removed to develop large-scale applications in electronics, catalysis, etc. In this regard, much effort to address such problems should be made to facilitate the evolution of the DNA origami technique and DNA origami-based nanofabrication, which might profoundly transform interdisciplinary fields, manufacturing and manufacturing methods.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

We acknowledge the funding provided by the Fundamental Research Funds for the Central Universities (grant no. 14380151).

References

  1. K. Rajagopal and J. P. Schneider, Curr. Opin. Struct. Biol., 2004, 14, 480–486 CrossRef CAS .
  2. K. S. Mali, K. Lava, K. Binnemans and S. De Feyter, Chemistry, 2010, 16, 14447–14458 CrossRef CAS .
  3. L. Yang, A. Liu, S. Cao, R. M. Putri, P. Jonkheijm and J. J. Cornelissen, Chemistry, 2016, 22, 15570–15582 CrossRef CAS .
  4. A. V. Pinheiro, D. Han, W. M. Shih and H. Yan, Nat. Nanotechnol., 2011, 6, 763–772 CrossRef CAS .
  5. N. C. Seeman and H. F. Sleiman, Nat. Rev. Mater., 2018, 3, 17068 CrossRef CAS .
  6. T. Torring, N. V. Voigt, J. Nangreave, H. Yan and K. V. Gothelf, Chem. Soc. Rev., 2011, 40, 5636–5646 RSC .
  7. P. Wang, T. A. Meyer, V. Pan, P. K. Dutta and Y. Ke, Chem, 2017, 2, 359–382 CAS .
  8. P. W. Rothemund, Nature, 2006, 440, 297–302 CrossRef CAS .
  9. L. Qian, Y. Wang, Z. Zhang, J. Zhao, D. Pan, Y. Zhang, Q. Liu, C. Fan, J. Hu and L. He, Chin. Sci. Bull., 2006, 51, 2973–2976 CrossRef CAS .
  10. S. M. Douglas, H. Dietz, T. Liedl, B. Hogberg, F. Graf and W. M. Shih, Nature, 2009, 459, 414–418 CrossRef CAS .
  11. H. Dietz, S. M. Douglas and W. M. Shih, Science, 2009, 325, 725–730 CrossRef CAS .
  12. E. S. Andersen, M. Dong, M. M. Nielsen, K. Jahn, R. Subramani, W. Mamdouh, M. M. Golas, B. Sander, H. Stark, C. L. Oliveira, J. S. Pedersen, V. Birkedal, F. Besenbacher, K. V. Gothelf and J. Kjems, Nature, 2009, 459, 73–76 CrossRef CAS .
  13. R. M. Zadegan, M. D. E. Jepsen, K. E. Thomsen, A. H. Okholm, D. H. Schaffert, E. S. Andersen, V. Birkedal and J. Kjems, ACS Nano, 2012, 6, 10050–10053 CrossRef CAS .
  14. D. Han, S. Pal, Y. Liu and H. Yan, Nat. Nanotechnol., 2010, 5, 712–717 CrossRef CAS .
  15. D. Han, S. Pal, J. Nangreave, Z. Deng, Y. Liu and H. Yan, Science, 2011, 332, 342–346 CrossRef CAS .
  16. D. Han, S. Pal, Y. Yang, S. Jiang, J. Nangreave, Y. Liu and H. Yan, Science, 2013, 339, 1412–1415 CrossRef CAS .
  17. E. Benson, A. Mohammed, J. Gardell, S. Masich, E. Czeizler, P. Orponen and B. Högberg, Nature, 2015, 523, 441–444 CrossRef CAS .
  18. R. Veneziano, S. Ratanalert, K. Zhang, F. Zhang, H. Yan, W. Chiu and M. Bathe, Science, 2016, 352, 1534 CrossRef CAS .
  19. R. Iinuma, Y. Ke, R. Jungmann, T. Schlichthaerle, J. B. Woehrstein and P. Yin, Science, 2014, 344, 65–69 CrossRef CAS .
  20. T. Gerling, K. F. Wagenbauer, A. M. Neuner and H. Dietz, Science, 2015, 347, 1446–1452 CrossRef CAS .
  21. Y. Ke, L. L. Ong, W. M. Shih and P. Yin, Science, 2012, 338, 1177–1183 CrossRef CAS .
  22. B. Wei, M. Dai and P. Yin, Nature, 2012, 485, 623–626 CrossRef CAS .
  23. F. Zhang, S. Jiang, S. Wu, Y. Li, C. Mao, Y. Liu and H. Yan, Nat. Nanotechnol., 2015, 10, 779–784 CrossRef CAS .
  24. K. F. Wagenbauer, C. Sigl and H. Dietz, Nature, 2017, 552, 78–83 CrossRef CAS .
  25. F. Hong, F. Zhang, Y. Liu and H. Yan, Chem. Rev., 2017, 117, 12584–12640 CrossRef CAS .
  26. D. Han, X. Qi, C. Myhrvold, B. Wang, M. Dai, S. Jiang, M. Bates, Y. Liu, B. An, F. Zhang, H. Yan and P. Yin, Science, 2017, 358, eaao2648 CrossRef .
  27. F. Praetorius, B. Kick, K. L. Behler, M. N. Honemann, D. Weuster-Botz and H. Dietz, Nature, 2017, 552, 84–87 CrossRef CAS .
  28. G. Tikhomirov, P. Petersen and L. Qian, Nature, 2017, 552, 67–71 CrossRef CAS .
  29. H. Ramezani and H. Dietz, Nat. Rev. Genet., 2020, 21, 5–26 CrossRef CAS .
  30. G. Yao, F. Zhang, F. Wang, T. Peng, H. Liu, E. Poppleton, P. Sulc, S. Jiang, L. Liu, C. Gong, X. Jing, X. Liu, L. Wang, Y. Liu, C. Fan and H. Yan, Nat. Chem., 2020, 12, 1067–1075 CrossRef .
  31. F. Liu, Y. Shang, Z. Wang, Y. Jiao, N. Li and B. Ding, APL Mater., 2020, 8, 110703 CrossRef CAS .
  32. J. Sharma, R. Chhabra, C. S. Andersen, K. V. Gothelf, H. Yan and Y. Liu, J. Am. Chem. Soc., 2008, 130, 7820–7821 CrossRef CAS .
  33. B. Ding, Z. Deng, H. Yan, S. Cabrini, R. N. Zuckermann and J. Bokor, J. Am. Chem. Soc., 2010, 132, 3248–3249 CrossRef CAS .
  34. S. Pal, Z. Deng, B. Ding, H. Yan and Y. Liu, Angew. Chem., Int. Ed., 2010, 49, 2700–2704 CrossRef CAS .
  35. A.-P. Eskelinen, R. J. Moerland, M. A. Kostiainen and P. Törmä, Small, 2014, 10, 1057–1062 CrossRef CAS .
  36. Z. Zhao, E. L. Jacovetty, Y. Liu and H. Yan, Angew. Chem., Int. Ed., 2011, 50, 2041–2044 CrossRef CAS .
  37. R. Schreiber, J. Do, E. M. Roller, T. Zhang, V. J. Schuller, P. C. Nickels, J. Feldmann and T. Liedl, Nat. Nanotechnol., 2014, 9, 74–78 CrossRef CAS .
  38. G. Yao, J. Li, J. Chao, H. Pei, H. Liu, Y. Zhao, J. Shi, Q. Huang, L. Wang, W. Huang and C. Fan, Angew. Chem., Int. Ed., 2015, 54, 2966–2969 CrossRef CAS .
  39. Y. Tian, T. Wang, W. Liu, H. L. Xin, H. Li, Y. Ke, W. M. Shih and O. Gang, Nat. Nanotechnol., 2015, 10, 637–644 CrossRef CAS .
  40. W. Liu, J. Halverson, Y. Tian, A. V. Tkachenko and O. Gang, Nat. Chem., 2016, 8, 867–873 CrossRef CAS .
  41. C. Shen, X. Lan, X. Lu, T. A. Meyer, W. Ni, Y. Ke and Q. Wang, J. Am. Chem. Soc., 2016, 138, 1764–1767 CrossRef CAS .
  42. P. Wang, S. Gaitanaros, S. Lee, M. Bathe, W. M. Shih and Y. Ke, J. Am. Chem. Soc., 2016, 138, 7733–7740 CrossRef CAS .
  43. H. Bui, C. Onodera, C. Kidwell, Y. Tan, E. Graugnard, W. Kuang, J. Lee, W. B. Knowlton, B. Yurke and W. L. Hughes, Nano Lett., 2010, 10, 3367–3372 CrossRef CAS .
  44. H. Zhang, M. Li, K. Wang, Y. Tian, J. S. Chen, K. T. Fountaine, D. DiMarzio, M. Liu, M. Cotlet and O. Gang, ACS Nano, 2020, 14, 1369–1378 CrossRef CAS .
  45. N. Li, Y. Shang, R. Xu, Q. Jiang, J. Liu, L. Wang, Z. Cheng and B. Ding, J. Am. Chem. Soc., 2019, 141, 17968–17972 CrossRef CAS .
  46. S. Jia, J. Wang, M. Xie, J. Sun, H. Liu, Y. Zhang, J. Chao, J. Li, L. Wang, J. Lin, K. V. Gothelf and C. Fan, Nat. Commun., 2019, 10, 5597 CrossRef CAS .
  47. Y. Shang, N. Li, S. Liu, L. Wang, Z. G. Wang, Z. Zhang and B. Ding, Adv. Mater., 2020, 32, e2000294 CrossRef .
  48. M. Wang, L. Dai, J. Duan, Z. Ding, P. Wang, Z. Li, H. Xing and Y. Tian, Angew. Chem., 2020, 59, 6389–6396 CrossRef CAS .
  49. X. Xin, L. Wang, K. Wang, L. Dai, H. Cao, Z. Li and Y. Tian, Chem. Commun., 2020, 56, 4918–4921 RSC .
  50. A. Kuzyk, R. Schreiber, Z. Fan, G. Pardatscher, E. M. Roller, A. Hogele, F. C. Simmel, A. O. Govorov and T. Liedl, Nature, 2012, 483, 311–314 CrossRef CAS .
  51. X. Shen, C. Song, J. Wang, D. Shi, Z. Wang, N. Liu and B. Ding, J. Am. Chem. Soc., 2012, 134, 146–149 CrossRef CAS .
  52. X. Shen, A. Asenjo-Garcia, Q. Liu, Q. Jiang, F. J. Garcia de Abajo, N. Liu and B. Ding, Nano Lett., 2013, 13, 2128–2133 CrossRef CAS .
  53. M. J. Urban, P. K. Dutta, P. Wang, X. Duan, X. Shen, B. Ding, Y. Ke and N. Liu, J. Am. Chem. Soc., 2016, 138, 5495–5498 CrossRef CAS .
  54. X. Lan, Z. Chen, G. Dai, X. Lu, W. Ni and Q. Wang, J. Am. Chem. Soc., 2013, 135, 11441–11444 CrossRef CAS .
  55. X. Lan, X. Lu, C. Shen, Y. Ke, W. Ni and Q. Wang, J. Am. Chem. Soc., 2015, 137, 457–462 CrossRef CAS .
  56. A. Kuzyk, R. Schreiber, H. Zhang, A. O. Govorov, T. Liedl and N. Liu, Nat. Mater., 2014, 13, 862–866 CrossRef CAS .
  57. C. Zhou, X. Duan and N. Liu, Nat. Commun., 2015, 6, 8102 CrossRef CAS .
  58. X. Lan, T. Liu, Z. Wang, A. O. Govorov, H. Yan and Y. Liu, J. Am. Chem. Soc., 2018, 140, 11763–11770 CrossRef CAS .
  59. R. Schreiber, N. Luong, Z. Fan, A. Kuzyk, P. C. Nickels, T. Zhang, D. M. Smith, B. Yurke, W. Kuang, A. O. Govorov and T. Liedl, Nat. Commun., 2013, 4, 2948 CrossRef .
  60. M. J. Urban, C. Zhou, X. Duan and N. Liu, Nano Lett., 2015, 15, 8392–8396 CrossRef CAS .
  61. A. Kuzyk, Y. Yang, X. Duan, S. Stoll, A. O. Govorov, H. Sugiyama, M. Endo and N. Liu, Nat. Commun., 2016, 7, 10591 CrossRef CAS .
  62. X. Lan, Z. Su, Y. Zhou, T. Meyer, Y. Ke, Q. Wang, W. Chiu, N. Liu, S. Zou, H. Yan and Y. Liu, Angew. Chem., Int. Ed., 2017, 56, 14632–14636 CrossRef CAS .
  63. T. Funck, F. Nicoli, A. Kuzyk and T. Liedl, Angew. Chem., Int. Ed., 2018, 57, 13495–13498 CrossRef CAS .
  64. A. Kuzyk, M. J. Urban, A. Idili, F. Ricci and N. Liu, Sci. Adv., 2017, 3, e1602803 CrossRef .
  65. N. Liu and T. Liedl, Chem. Rev., 2018, 118, 3032–3053 CrossRef CAS .
  66. M. Wang, J. Dong, C. Zhou, H. Xie, W. Ni, S. Wang, H. Jin and Q. Wang, ACS Nano, 2019, 13, 13702–13708 CrossRef CAS .
  67. Q. Jiang, Q. Liu, Y. Shi, Z. G. Wang, P. Zhan, J. Liu, C. Liu, H. Wang, X. Shi, L. Zhang, J. Sun, B. Ding and M. Liu, Nano Lett., 2017, 17, 7125–7130 CrossRef CAS .
  68. L. Xin, C. Zhou, X. Duan and N. Liu, Nat. Commun., 2019, 10, 5394 CrossRef .
  69. S. Laing, L. E. Jamieson, K. Faulds and D. Graham, Nat. Rev. Chem., 2017, 1, 0060 CrossRef CAS .
  70. J. Prinz, B. Schreiber, L. Olejko, J. Oertel, J. Rackwitz, A. Keller and I. Bald, J. Phys. Chem. Lett., 2013, 4, 4140–4145 CrossRef CAS .
  71. V. V. Thacker, L. O. Herrmann, D. O. Sigle, T. Zhang, T. Liedl, J. J. Baumberg and U. F. Keyser, Nat. Commun., 2014, 5, 3448 CrossRef .
  72. P. Kuhler, E. M. Roller, R. Schreiber, T. Liedl, T. Lohmüller and J. Feldmann, Nano Lett., 2014, 14, 2914–2919 CrossRef .
  73. S. Simoncelli, E. M. Roller, P. Urban, R. Schreiber, A. J. Turberfield, T. Liedl and T. Lohmuller, ACS Nano, 2016, 10, 9809–9815 CrossRef CAS .
  74. M. Pilo-Pais, A. Watson, S. Demers, T. H. LaBean and G. Finkelstein, Nano Lett., 2014, 14, 2099–2104 CrossRef CAS .
  75. S. Tanwar, K. K. Haldar and T. Sen, J. Am. Chem. Soc., 2017, 139, 17639–17648 CrossRef CAS .
  76. P. Zhan, T. Wen, Z. G. Wang, Y. He, J. Shi, T. Wang, X. Liu, G. Lu and B. Ding, Angew. Chem., Int. Ed., 2018, 57, 2846–2850 CrossRef CAS .
  77. W. Fang, S. Jia, J. Chao, L. Wang, X. Duan, H. Liu, Q. Li, X. Zuo, L. Wang, L. Wang, N. Liu and C. Fan, Sci. Adv., 2019, 5, eaau4506 CrossRef .
  78. Y. Matsumura and H. Maeda, Cancer Res., 1986, 46, 6387–6392 CAS .
  79. Y. Noguchi, J. Wu, R. Duncan, J. Strohalm, K. Ulbrich, T. Akaike and H. Maeda, Jpn. J. Cancer Res., 1998, 89, 307–314 CrossRef CAS .
  80. H. Maeda, Bioconjugate Chem., 2010, 21, 797–802 CrossRef CAS .
  81. J. Fang, H. Nakamura and H. Maeda, Adv. Drug Delivery Rev., 2011, 63, 136–151 CrossRef CAS .
  82. H. Maeda, Adv. Drug Delivery Rev., 2015, 91, 3–6 CrossRef CAS .
  83. I. Brigger, C. Dubernet and P. Couvreur, Adv. Drug Delivery Rev., 2002, 54, 631–651 CrossRef CAS .
  84. S. Acharya and S. K. Sahoo, Adv. Drug Delivery Rev., 2011, 63, 170–183 CrossRef CAS .
  85. I. Brigger, C. Dubernet and P. Couvreur, Adv. Drug Delivery Rev., 2012, 64, 24–36 CrossRef .
  86. D. Kalyane, N. Raval, R. Maheshwari, V. Tambe, K. Kalia and R. K. Tekade, Mater. Sci. Eng., C, 2019, 98, 1252–1276 CrossRef CAS .
  87. S. Mishra, Y. Feng, M. Endo and H. Sugiyama, ChemBioChem, 2020, 21, 33–44 CrossRef CAS .
  88. Y. X. Zhao, A. Shaw, X. Zeng, E. Benson, A. M. Nystrom and B. Högberg, ACS Nano, 2012, 6, 8684–8691 CrossRef CAS .
  89. Q. Jiang, C. Song, J. Nangreave, X. Liu, L. Lin, D. Qiu, Z. G. Wang, G. Zou, X. Liang, H. Yan and B. Ding, J. Am. Chem. Soc., 2012, 134, 13396–13403 CrossRef CAS .
  90. Q. Zhang, Q. Jiang, N. Li, L. Dai, Q. Liu, L. Song, J. Wang, Y. Li, J. Tian, B. Ding and Y. Du, ACS Nano, 2014, 8, 6633–6643 CrossRef CAS .
  91. J. Vollmer and A. M. Krieg, Adv. Drug Delivery Rev., 2009, 61, 195–204 CrossRef CAS .
  92. V. J. Schuller, S. Heidegger, N. Sandholzer, P. C. Nickels, N. A. Suhartha, S. Endres, C. Bourquin and T. Liedl, ACS Nano, 2011, 5, 9696–9702 CrossRef .
  93. M. A. Rahman, P. Wang, Z. Zhao, D. Wang, S. Nannapaneni, C. Zhang, Z. Chen, C. C. Griffith, S. J. Hurwitz, Z. G. Chen, Y. Ke and D. M. Shin, Angew. Chem., Int. Ed., 2017, 56, 16023–16027 CrossRef CAS .
  94. S. Zhao, F. Duan, S. Liu, T. Wu, Y. Shang, R. Tian, J. Liu, Z. G. Wang, Q. Jiang and B. Ding, ACS Appl. Mater. Interfaces, 2019, 11, 11112–11118 CrossRef CAS .
  95. S. Li, Q. Jiang, S. Liu, Y. Zhang, Y. Tian, C. Song, J. Wang, Y. Zou, G. J. Anderson, J. Y. Han, Y. Chang, Y. Liu, C. Zhang, L. Chen, G. Zhou, G. Nie, H. Yan, B. Ding and Y. Zhao, Nat. Biotechnol., 2018, 36, 258–264 CrossRef CAS .
  96. M. Lan, S. Zhao, W. Liu, C. S. Lee, W. Zhang and P. Wang, Adv. Healthcare Mater., 2019, 8, e1900132 CrossRef .
  97. X. Zhuang, X. Ma, X. Xue, Q. Jiang, L. Song, L. Dai, C. Zhang, S. Jin, K. Yang, B. Ding, P. C. Wang and X. J. Liang, ACS Nano, 2016, 10, 3486–3495 CrossRef CAS .
  98. Y. Du, Q. Jiang, N. Beziere, L. Song, Q. Zhang, D. Peng, C. Chi, X. Yang, H. Guo, G. Diot, V. Ntziachristos, B. Ding and J. Tian, Adv. Mater., 2016, 28, 10000–10007 CrossRef CAS .
  99. J. Liu, L. Song, S. Liu, S. Zhao, Q. Jiang and B. Ding, Angew. Chem., Int. Ed., 2018, 57, 15486–15490 CrossRef CAS .
  100. J. Liu, L. Song, S. Liu, Q. Jiang, Q. Liu, N. Li, Z. G. Wang and B. Ding, Nano Lett., 2018, 18, 3328–3334 CrossRef CAS .
  101. Q. Pan, C. Nie, Y. Hu, J. Yi, C. Liu, J. Zhang, M. He, M. He, T. Chen and X. Chu, ACS Appl. Mater. Interfaces, 2020, 12, 400–409 CrossRef CAS .
  102. P. Wang, M. A. Rahman, Z. Zhao, K. Weiss, C. Zhang, Z. Chen, S. J. Hurwitz, Z. G. Chen, D. M. Shin and Y. Ke, J. Am. Chem. Soc., 2018, 140, 2478–2484 CrossRef CAS .
  103. M. M. C. Bastings, F. M. Anastassacos, N. Ponnuswamy, F. G. Leifer, G. Cuneo, C. Lin, D. E. Ingber, J. H. Ryu and W. M. Shih, Nano Lett., 2018, 18, 3557–3564 CrossRef CAS .
  104. C. Wiraja, Y. Zhu, D. C. S. Lio, D. C. Yeo, M. Xie, W. Fang, Q. Li, M. Zheng, M. Van Steensel, L. Wang, C. Fan and C. Xu, Nat. Commun., 2019, 10, 1147 CrossRef .
  105. L. Song, Q. Jiang, J. Liu, N. Li, Q. Liu, L. Dai, Y. Gao, W. Liu, D. Liu and B. Ding, Nanoscale, 2017, 9, 7750–7754 RSC .
  106. Z. Ge, L. Guo, G. Wu, J. Li, Y. Sun, Y. Hou, J. Shi, S. Song, L. Wang, C. Fan, H. Lu and Q. Li, Small, 2020, 16, e1904857 CrossRef .
  107. R. Chen, P. Sun, X. Chu, X. Pu, Y. Yang, N. Zhang and Y. Zhao, Int. J. Nanomed., 2020, 15, 1309–1320 CrossRef CAS .
  108. D. H. Schaffert, A. H. Okholm, R. S. Sorensen, J. S. Nielsen, T. Torring, C. B. Rosen, A. L. Kodal, M. R. Mortensen, K. V. Gothelf and J. Kjems, Small, 2016, 12, 2634–2640 CrossRef CAS .
  109. J. Hahn, S. F. Wickham, W. M. Shih and S. D. Perrault, ACS Nano, 2014, 8, 8765–8775 CrossRef CAS .
  110. A. Rajendran, M. Endo, Y. Katsuda, K. Hidaka and H. Sugiyama, J. Am. Chem. Soc., 2011, 133, 14488–14491 CrossRef CAS .
  111. V. Cassinelli, B. Oberleitner, J. Sobotta, P. Nickels, G. Grossi, S. Kempter, T. Frischmuth, T. Liedl and A. Manetto, Angew. Chem., Int. Ed., 2015, 54, 7795–7798 CrossRef CAS .
  112. N. Ponnuswamy, M. M. C. Bastings, B. Nathwani, J. H. Ryu, L. Y. T. Chou, M. Vinther, W. A. Li, F. M. Anastassacos, D. J. Mooney and W. M. Shih, Nat. Commun., 2017, 8, 15654 CrossRef CAS .
  113. F. M. Anastassacos, Z. Zhao, Y. Zeng and W. M. Shih, J. Am. Chem. Soc., 2020, 142, 3311–3315 CrossRef CAS .
  114. J. Mikkila, A. P. Eskelinen, E. H. Niemela, V. Linko, M. J. Frilander, P. Torma and M. A. Kostiainen, Nano Lett., 2014, 14, 2196–2200 CrossRef CAS .
  115. H. Auvinen, H. Zhang, Nonappa, A. Kopilow, E. H. Niemela, S. Nummelin, A. Correia, H. A. Santos, V. Linko and M. A. Kostiainen, Adv. Healthcare Mater., 2017, 6, 1700692 CrossRef .
  116. S.-T. Wang, M. A. Gray, S. Xuan, Y. Lin, J. Byrnes, A. I. Nguyen, N. Todorova, M. M. Stevens, C. R. Bertozzi, R. N. Zuckermann and O. Gang, Proc. Natl. Acad. Sci. U. S. A., 2020, 117, 6339–6348 CrossRef CAS .
  117. S. D. Perrault and W. M. Shih, ACS Nano, 2014, 8, 5132–5140 CrossRef CAS .
  118. R. Ranjbar and M. S. Hafezi-Moghadam, Electron Physician, 2016, 8, 1857–1864 CrossRef .
  119. D. Jiang, Z. Ge, H. J. Im, C. G. England, D. Ni, J. Hou, L. Zhang, C. J. Kutyreff, Y. Yan, Y. Liu, S. Y. Cho, J. W. Engle, J. Shi, P. Huang, C. Fan, H. Yan and W. Cai, Nat. Biomed. Eng., 2018, 2, 865–877 CrossRef CAS .

Footnote

† These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2021
Click here to see how this site uses Cookies. View our privacy policy here.