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Recent progress on DNA block copolymer
Accepted Manuscript Title: Recent progress onPlease check ¨ the doc head Review¨ and correct if necessary.–> DNA block copolymer Authors: Gaifang Pan, Xin Jin, Quanbing Mou, Chuan Zhang PII: DOI: Reference:
S1001-8417(17)30307-8 http://dx.doi.org/10.1016/j.cclet.2017.08.022 CCLET 4171
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Chinese Chemical Letters
Please cite this article as: Gaifang Pan, Xin Jin, Quanbing Mou, Chuan Zhang, Recent progress on DNA block copolymer, Chinese Chemical Lettershttp://dx.doi.org/10.1016/j.cclet.2017.08.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Review
Recent progress on DNA block copolymer Gaifang Pan1, Xin Jin1, Quanbing Mou*, Chuan Zhang* School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China
Corresponding authors. E-mail addresses: [email protected] (Q. Mou), [email protected] (C. Zhang). 1
These authors contributed equally to this work.
Graphical Abstract
Organic polymers are combined with DNA resulting DNA block copolymers (DBCs) that can simultaneously show the properties of the polymer and DNA. We will discuss some examples of recent developments in the syntheses, structure manipulations, and applications of DBCs.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
DNA has gained great attention because of its unique structure, excellent molecular recognition property, and biological functions. When married with versatile synthetic polymers, the DNA conjugated polymer hybrids, known as DNA block copolymers (DBCs), have been launched and well developed for the syntheses of new materials and nanostructures with different functions in the past several decades. Compared to conventional synthetic block copolymers, using DNA as a building block provides several advantages over other polymer candidates, such as molecular recognition, programmable self-assembly, biocompatibility, and sequence-encoded information. In this mini-review, recent developments in this area will be summarized and meaningful breakthroughs will be highlighted. We will discuss representative examples of recent progress in the syntheses, structure manipulations, and applications of DBCs.
Keywords: DNA block copolymer Self-assembly Nanostructure Hybrid material Micelle
1. Introduction In polymer science, block copolymers have aroused great interest due to their controllable structures and tailorable properties [15]. Owing to the existence of varied segments in a polymer chain, block copolymers and their assemblies exhibit unique properties that are different from their homopolymer counterparts [6-10]. It is well-known that the properties and assembly behaviors of block copolymer are highly related to the chemical nature of its component monomers, the length of each block, and the ratio of block length. However, conventional block polymers that consist of multitude of synthetic polymer segments are lack of precise molecular weight and ordered primary structures for each block, impeding the precise control over their assembling behaviors. Alternatively, nature synthesizes a large variety of biopolymers day and night, which usually have precise lengths and well-defined structures. To construct more useful block copolymers, integrating a precise biomacromolecule as one building block is a feasible way to synthesize novel block copolymers, which can bring the hybrid structures with new properties.
As one of the most important biomacromolecules, DNA can be particularly designed and conjugated with synthetic polymers to form DNA block polymers, named as DBCs [11-30]. Upon consisting of DNA segments, the DBCs behave in both DNA way and polymer way. Particularly, DNA is famous for its double helix structure and the well-known Watson-Crick base pairing [31]. Besides its biological roles, DNA can also be utilized as a generical polymer for new material synthesis based on its excellent molecular recognition and programmable self-assembly power, which has been witnessed by the fast development of “structural DNA nanotechnology” [32-38]. Thus, introducing the DNA segment into block copolymer will bring the DBCs with many hallmark properties that never exist in conventional block copolymers, including accurate chemical structure segment, specific self-assembly driving force, and molecular recognition, etc. Although the synthesis of the first DBC construct can be traced back to the late 1980s [39], this new class of material receive increasing attention and become a popular candidate for novel nanostructure design and construction particularly in the past two decades [40-42]. In general, by appropriate selecting organic polymer and engineering the DNA sequence, the properties and functions of DBC materials can be well-controlled for designated applications. For instance, conjugating hydrophilic polymer results in water-soluble DBCs, which are widely used for hydrogel formation [43]. In contrast, introducing a hydrophobic polymer into DBCs will generate a block copolymer with amphiphilic feature, which can self-assemble into micellar structures with hydrophobic core inside and hydrophilic DNA corona at the surface, enabling them as ideal carrier for drug delivery [44,45]. Moreover, the functions of DBCs are often contributed from all block segments synergistically. On one hand, plenty of synthetic polymers with unique properties can be selected to design functional DBCs. For example, the polymers that are responsive to stimuli such as pH, temperature, light, or salt concentration changes, can endow the DBCs with corresponding stimuliresponsive properties. On the other hand, DNA segments can also bring the DBCs remarkable functions that are linked to their welldefined primary structures, sequence-encoded biological potentials, and molecular recognitions. Along this direction, DBCs and their assemblies have been widely applied for gene or oligodeoxyribonucleotide (ODN) delivery [44,46]. In addition, DNA blocks can also be used to drive the self-assembly in a controllable and precise way for polymer assembly system, resulting in the rational design of various functional nanostructures [47]. Notably, there are plenty of differences between polymer chains and DNA segments, such as synthetic route, solubility, molecular weight and distribution, topology, and self-assembly behaviors [48-52]. Thus, how to balance these differences and controversy is a key issue in designing DBCs materials. Moreover, the controlled syntheses of sophisticated nanostructures with specific functions is always the centre of undergoing DBC related researches. In this mini review, we will briefly review the researches on DBCs in recent years, hoping to provide academic help and share opinions to whom have interests on this topic. In Section 2, we will simply describe several approaches to prepare DBCs, such as solution coupling, solid coupling, and molecular biology strategy. In Section 3, we will focus on introducing the principles and regulations in DBCs self-assembly and recent advances in the obtained nanostructures. Finally, applications of DBCs in different areas will be summarized, such as nanocarriers for drug delivery, chemical reaction templates, 3D printing materials, and nanoelectronics, which are shown in Section 4. 2. Synthesis of DNA block copolymer (DBCs) 2.1. Solution coupling As a typical macromolecule, DNA has inherent molecular order, specific sequence information, and precise molecular weight. Different from most synthetic macromolecules, all DNA materials are totally hydrophilic. Therefore, the first generation of DBCs is synthesized in aqueous solution through click reaction, Michael addition, disulfide bond formation [47,53-59], etc. For example, as a typical type of hydrophilic polymer, peptides have been grafted to DNA through a copper(I)-catalyzed click reaction [55,58]. Moreover, the Michael addition is another approach for the attachment of ODNs to hydrophilic polymers. In this approach, acrylatefunctionalized polymer moieties and thiol-modified ODNs serve as Michael acceptors and Michael donors, respectively [46,59]. Comparatively, DNA segment can hardly dissolve in most organic solvents, which usually leads to low yields of the coupling reaction with a wide range of hydrophobic polymers. As such, modification strategies mentioned above are almost prohibitive for conjugating DNA strands to hydrophobic polymers and the synthesis of DBCs consisting of hydrophobic polymer blocks remains as a big challenge for a long period. To solve this problem, Herrmann and coworkers introduced a DNA-surfactant complex as a reactive scaffold to increase the solubility of DNA segment in organic solution and then successfully establish the organic-phase coupling strategy for DBC syntheses [60]. This surfactant-assisted synthesis strategy has been verified as an effective approach in coupling the ODN to remarkable range of hydrophobic polymers, including poly (propylene oxide) (PPO), polyisoprene (PI), and polystyrene (PS), etc. For example, the synthesis of the ODN-b-PPO (2.5k) block copolymer in organic solvent following the procedure is depicted in Fig. 1 [60]. Moreover, this strategy can be further extended for producing a series of new brush-type of DNA-grafted homopolymers through direct polymerization, shedding new lights for the access of DBCs with more complex structures and functions [52].
Fig. 1. Scheme of the organic-phase synthesis of functional DNA, and DBCs employing activated esters. Reproduced with permission [60]. Copyright 2014, American Chemical Society.
2.2. Solid-phase coupling Although surfactant-assisted synthesis enables the effective DNA conjugation with hydrophobic polymers, surfactants used in the system are usually difficult to be totally removed, which brings purity and safety concerns to the resulting DBCs. Later, solid phase coupling was developed to synthesize DNA/hydrophobic polymer conjugates with high yield, as well as high purity. In general, the amphiphilic DBCs synthesized through solid-phase coupling were prepared by well-established phosphoramidite chemistry and syringe synthesis technique [61]. Due to the efficient exposure of excess phosphoramidite polymer and the high reproducibility of the solid-phase synthesis, DBCs could be prepared in a fully “in line” automated approach [45], which has significant superiority in comparison to a chemical grafting approach in aqueous solution. The automated DNA synthesizer is employed in the synthesis of functionalized DNA. Terminal functionalization can be integrated into the automated synthesis protocol mostly through phosphoramidite chemistry (Fig. 2). Tan and coworkers developed similar synthetic method for coupling oligonucleotides to conjugated polyelectrolytes [62]. Alternatively, post-synthetic modification may be carried out on the solid support outside of the synthesizer. More recently, Matyjaszewski and coworkers developed another robust way to synthesize DBCs via photochemically mediated atom transfer radical polymerization (photo-ATRP) on a DNA synthesizer. Interestingly, both hydrophobic and hydrophilic monomers could be grafted from DNA to form DBCs [63]. Although many DBCs have been synthesized through solid-phase synthetic routes, it is worth noting that this strategy also has some limitations. For example, solvent selection is taken special care due to solvent-dependent swelling properties of cross-linked polymer resins [45]. Moreover, the overall coupling yield will dramatically decrease when a long DNA strand is going to be synthesized, which impedes the synthesis of DBCs with long DNA blocks. Importantly, functional groups introduced on the building block must be stable against the deprotection conditions.
Fig. 2. Cartoon representation of DNA block hydrophobic polymer through solid-phase synthesis (a) and their assemblies (b and c). Reproduced with permission [30]. Copyright 2004, American Chemical Society.
2.3. Molecular biology techniques In an organism, DNA usually exists as long duplexes to encode the genetic information and nature develops specific proteins to synthesize, cut, and manipulate these gene carriers. To construct the DBCs with a longer DNA block, advanced molecular biology techniques can also be used to synthesize the required DNA segments. Polymerase chain reaction (PCR) as well as enzymatic restriction and ligation are the versatile and general tools for the synthesis and manipulation of DNA chains. Recently, PCR technique has been used to synthesize well-defined DNA block copolymer architectures [64]. Di-block copolymer can be obtained by using one single-stranded DNA block copolymer and one oligonucleotide as primers. When two single-stranded DNA block copolymers and one oligonucleotide are used as primers, a tri-block polymer can be constructed (Fig. 3) [47]. With the help of PCR
technique, complicated DNA block polymer with ultrahigh molecular weight and multi-block copolymers with perfect structural composition could be obtained.
Fig. 3. Schematic representation of the build-up of DBCs by using PCR strategy. Reproduced with permission [47]. Copyright 2012, American Chemical Society.
Compared with the PCR approach, it is also possible for enzymatic restriction and ligation to produce the extended DBCs with extremely high molecular weight (~ three million Daltons). By utilizing the DNA restriction enzyme, three double stranded DNA segments with different lengths were synthesized [64]. Then, DBCs with controllable DNA length were synthesized in a one-pot method, through simple mixing and incubation with T4 DNA ligation enzyme (Fig. 4) [64]. Different from chemical coupling strategies mentioned above, this strategy has greatly broadened a wide range of synthetic approaches to construct the DBCs, in which long DNA segments may be equipped with unique and accurate chain information, paving a new avenue for the design and synthesis of DBC-based functional materials.
Fig. 4. Schematic representation of enzymatic restriction and ligation to synthesize DBCs. Reproduced with permission [47]. Copyright 2012, American Chemical Society.
3. DBCs self-assembly and morphology control Owing to consisting of multitude components, the self-assembly behaviors of DBCs are attractive where supramolecular assembly can occur either based on molecular recognition of DNA segments or amphiphilic/electronic interactions in polymer segments. In particular, DNA segments with precise sequence and primary structure exhibit excellent spatial addressability, which further facilitate supramolecular assembly of DBCs. As such, a wide range of nanostructures with various morphologies and functions have been created in the past two decades and we will enumerate some of the recent cases as below. 3.1. Morphology design and control The shape and size distribution of DBCs can be manipulated by regulating the structure nature of DNA segment or polymer segment. For example, the shape of DBCs micelles could be switched between spherical and rod-like aggregates by changing the length of antisense oligonucleotides and designing the template that encodes the complementary sequence of DBCs corona [65]. Most recently, DBCs have been highlighted for opening new routes to construct more complex nanostructures, such as hollowed vesicles. As shown in Fig. 5, when conjugating the DNA with poly[3-(2,5,8,11-tetraoxatridecanyl)thiophene] (PTOTT) by phosphoramidite chemistry, the resulting amphiphilic DNA-b-PTOTT could assemble into vesicles in aqueous solution where DNA acted as the hydrophilic chain and the polymer aggregated in a tense way through hydrophobic interaction as well as π-π stacking [66]. This work suggested that regulation of polymer property could also effectively control the morphology of DBCs’ assemblies. Furthermore, DNA-b-PTOTT can be used to co-assemble with PEG-b-PTOTT (polyethylene glycol (PEG)). With an appropriate ratio, one-dimensional PTOTT nano-ribbons modified with DNA could be realized. As PTOTT is a good semiconducting polymer, the synthesized one-dimensional ribbon may demonstrate potentials in plastic electronics and flexible devices.
Fig. 5. Schematic depiction of the self-assembly of DNA-b-PTOTT into vesicles. Reproduced with permission from [66]. Copyright 2014, American Chemical Society.
The morphology of nanostructure can be regulated not only by driving force but also by specific thermal treatment during the selfassembly process. One successful example is the supramolecular self-assembly of DBC polymer composed of an oligopyrenotide chain and a DNA segment. The degree of order and tightness of pyrene can be increased by using the nucleation-elongation process, resulting in the formation of helical nano-ribbon. In this system, hydrophobic and stacking interactions are the major driving force for pyrene aggregation and elongation, while multi-step thermal treatments at different temperature can force pyrene tensely to be aligned and self-assembled, tuning the lengths of nanoribbons ranging from 50 nm to 500 nm. Importantly, DNA segments distributed around the nano-ribbon still keep their functions (Fig. 6) [67].
Fig. 6. Formation of helical nano-ribbons through nucleation–elongation process of DBCs. Reproduced with permission from [67]. Copyright 2015, WileyVCH.
3.2. Hierarchical and hyper-dimension nanostructures The dimension of nanostructure has not been deeply discussed in other self-assembly systems. In DBCs systems, however, it is feasible to form hierarchical diverse dimensional assemblies due to the existence of multitude driving forces during the self-assembly [68,69]. Indeed, the unique self-recognition properties of DNA allow the DBCs to form hyper-dimensional nanostructures with amazing sophisticated and complex structure, which are not easy to be realized by other means. In this field, Sleiman and co-workers recently developed a DBC by covalently attaching three polymer chains to a DNA strand via ring-opening metathesis polymerization. DNA segments with specific designed sequences can assembled into well-defined DNA nanocage and spontaneously drag tri-block polymer attach to the desired sites on the DNA nanostructure. Importantly, the number and position of the attached polymers could be feasibly regulated (Fig. 7) [70], allowing the polymer-coated DNA cages more resistant to the nuclease compared to those of uncoated DNA structures. Furthermore, this well-defined 3D-DNA “frame” can be used as building blocks to create hyper-dimensional core-shell hybrid assemblies. For instance, by varying the position and multiplicity of the hydrophobic precision polymers on the DNA nanocage, So-Jung and his coworkers further assembled these polymer-addressable 3D DNA cages into highly ordered superstructures. With the tunable geometry of polymer-attached DNA cage units, a library of larger, functional DNA nanostructures could be constructed in an orthogonal assembly manner [71]. This achievement is the first exploration of tuning the interface of precision polymers and DNA nanostructures for constructing hierarchical DBC superstructures. And it could be expected that more exciting and functional structures can be expected to arise from this method.
Fig. 7. Schematic representations of organizing DNA-polymer conjugate onto 3D DNA cubes scaffold. Reproduced with permission [70]. Copyright 2012, American Chemical Society.
Similar to traditional hydrophobic polymers, responsive polymers can also be used as the driving force for secondary selfassembly to form hyper-dimensional nanostructure. Sleiman and his coworkers chose the typical temperature responsive polymer poly(N-isoproylacrylamide) (poly(NIPAM)) as a block to regulate the self-assembly behavior of DBC. At the temperature below the lower critical solution temperature (LCST), poly(NIPAM)-block-DNA can dissolve in the aqueous solution and assemble into a tetrahedron with polymer tails outside. Upon the temperature is higher than the LCST, poly(NIPAM) segments turn into hydrophobic and drive the polymer-DNA cages to form micellar superstructure with tetrahedrons on the surface (Fig. 8) [72]. Acting as the secondary well-defined nanostructure as well as the stabilizers for poly(NIPAM) micelles, DNA tetrahedrons may be further engineered with functional moieties and bring the thermal-responsive superstructure with new features.
Fig. 8. Schematic representations of synthesizing polymer-DNA tetrahedron conjugate and temperature-induced formation of micellar superstructure from poly(NIPAM) attached DNA tetrahedron. Reproduced with permission [72]. Copyright 2013, American Chemical Society.
4. Applications Natural nucleic acids are easily to be hydrolyzed through enzymatic degradation in biological environment, which greatly limits their practical applications for in vivo detection and therapeutic purposes. To solve the problem, DNA analogues have been designed and synthesized with unpredictable off-target effects [73], or with precluding advantageous interactions with key cellular machinery [25,74] which is capable of enzyme-resistance [75]. In a typical DBC assembly, DNA usually acts as the polar head group of DBCs, while polymer block acts as the basic skeleton. Previous studies found that dense packing of DNA in the micelle corona could be achieved through regulation of the polymer segment, with which nuclease cannot reach nucleic acids resulting in a relatively “safe” surrounding from enzymatic degradation during the blood circulation (Fig. 9) [73]. Moreover, the biodegradability and biocompatibility of DNA make them attractive for biomedical applications [76,77]. Specifically, these biodegradable DBCs can internalize into the cells more efficiently than the pristine synthetic oligonucleotides [77]. Thus, DBC-based assemblies capable of enzyme-resistance were widely used in gene regulation, drug delivery, 3D printing, and nanoelectronics, etc.
Fig. 9. Schematic representation of nuclease resistance of DNA-polymer amphiphile nanoparticles. Reproduced with permission [73]. Copyright 2013, American Chemical Society.
4.1. Gene regulation
The utility of DNA in biological application develops rather fast in recent years. Especially, some de novo nanostructures such as spherical nucleic acids (SNAs) exhibit a variety of novel properties that are substantively different from their linear nucleic acid counterparts, making them attractive for intracellular applications. As we know, DNA can act as both delivery material and sequence-dependent therapeutic agents. Thus, involving polymer micelle structures with a dense layer of therapeutic nucleic acids for intracellular gene regulation will be fascinating. For instance, recently we developed a micelle-SNA derived from the DNA brush block copolymer (DBBC). With high dense layer of nucleic acids on its surface, DBBC-based SNA can internalize into the cells more effectively compared to that of the linear DBC assembly even without the use of transfection agents. By designing the DNA to be anti-EGFP antisense sequence, DBBC-based SNA with good biocompatibility and biodegradability show effective target gene knockdown in vitro (Fig. 10) [44]. This DBC-based approach can be extended to deliver various nucleic acid-based therapeutics.
Fig. 10. The synthesis of DNA grafted block copolymer-based micelle-SNAs (a) and gene regulation by DBBC-based micelle-SNAs (b). Reproduced with permission [44]. Copyright 2015, Wiley-VCH.
4.2. Drug delivery Apart from gene therapy, a variety of DNA-based systems have been constructed for cancer therapy, biosensing, and detection. Here we will first introduce a typical strategy of DNA-based delivery system with DNA conjugated to chemotherapeutics for cancer therapy. A library of hydrophobic drugs can be attached to DNA segment, and the amphiphilicity of the DBCs conjugates allows them to assemble into micellar nanostructures for drug delivery. This strategy is feasible with great diversities. However, one major problem is the drug release issue. To overcome this barrier, as shown in Fig. 11, stimuli-responsive breakable linkage was introduced into DNA-drug conjugates [78]. DNA-camptochecin (CPT) was synthesized as a drug-cored nucleic acid nanostructure containing hydrophobic CPT as chemotherapeutic agents. Upon UV light (365 nm), the 2-nitrobenzyl group can be cleaved, releasing the DNA segment from the nanostructure and leaving a decapped self-immolative drug core for further treatment. This approach has provided a feasible method to control drug release behavior. Similarly, Herrmann and coworkers developed a novel function of DNA-lipid vesicle system for selective cargo release from lipid vesicles based on amphiphilic DBCs and the hybridization of photosensitizer units. Thus, the delivery system could release cargo through physicochemical responses to light irradiation [79]. What’s more, DBC-based hybrid nanoparticles can be used to co-deliver DOX and PTX with high specificity and efficiency [80].
Fig. 11. Schematics of the DNA-drug nanostructures assembled from photolabile DNA-drug amphiphiles. Reproduced with permission from [78]. Copyright 2015, American Chemical Society.
4.3. 3D printing 3D printing has drawn great attention in tissue engineering as a powerful fabrication method to design and create tissue-like structures. Particularly for 3D bioprinting, biodegradable and biocompatible scaffold materials, such as hydrogel [82], are critical to
be used as the bio-inks. Liu and coworkers reported the rapid formation of a supramolecular polypeptide-DNA hydrogel as the bioink, which was subsequently used for in situ multilayer 3D bioprinting (Fig. 12) [81]. The printed hydrogels possess excellent healing and can keep their shapes up to the millimeter scale without collapse. Such a biocompatible and biodegradable hydrogel is a new promising printable biomaterial for the fabrication of complex three-dimensional tissue-like constructs for tissue engineering.
Fig. 12. 3D bioprinting of polypeptide-DNA hydrogels with AtT-20 cells. Reproduced with permission [81]. Copyright 2015, Wiley-VCH.
4.4. Nanoelectronics Synthetic DNA tends to self-assemble into nanoparticles with high order and multi-hole structures, which makes DBCs a popular choice for conducting polymer templates and nanoelectronics applications. After complex with SWNTs, an amphiphilic DBC consisting of poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO) block and 22mer single-stranded OND was applied to help SWNTs locate on the substrate (Fig. 13) [83]. This might be the first success for site-specifically immobilizing individual carbon nanotube in a programmed and large-scale way. Recently, Herrmann and coworkers took advantage of the interactions for the self-assembly of field-effect transistors from semiconducting single-walled carbon nanotubes selectively dispersed by DBCs and anchored to the electrodes through DNA hybridization. These transistors could sensitively detect the hybridization of complementary target DNA strands through transduction of the chemical recognition event into electrical doping, yielding an analyte sensitivity of 10 fmol/L. Such ultra-sensitive electrical-based detection offered a fantastic way to nucleic acids diagnostics with no need for DNA amplification [84].
Fig. 13. Complex DBCs with SWNTs and its application in nanoelectronics. Reproduced with permission [83]. Copyright 2011, Wiley-VCH.
5. Conclusion As a novel hybrid material, DBCs behave in a higher level of controllability than the other kinds of block copolymers, due to DNA’s unique self-assembly property. Through molecular recognition powered by the DNA segments, novel architectures become assessable in a DNA-directed self-assembly manner. Compared to assemblies from synthetic polymers only, nanostructures assembled by DBCs are of high tunability, hyper-dimension, and multi-functions. Therefore, the potential applications of these unique materials and their assemblies are located in a broad range of areas, such as drug delivery, complex nanostructure fabrication,
nanosized sensors, and high performance nanoelectronics [85-87]. With the fast development of new coupling techniques that can effectively conjugate the DNA with hydrophilic and hydrophobic polymers, we believe more DBCs with a broad range of properties and functions will be synthesized for more high-tech applications. As highly tunable and functional materials, the segments in DBCs can be further engineered in future. For instance, organic polymer with stimuli-responsive properties can be expected for constructing smart nanomaterials for bionanotechnology. Meanwhile, a broad range of chemical and biological techniques can be used for the modification of DNA blocks, which will give access to new materials with more biological functions. Nevertheless, some challenges remain in this promising field. For instance, there is lack of a universal approach to fabricate different types of DBCs even though various synthetic strategies have been established as mentioned above. In addition, the high local DNA concentration of DBC assemblies might cause immune response for in vivo applications, which may be overcome through de novo design of DNA sequences. Despite these challenges, great opportunities still exist for researchers in this emerging area and we believe more breakthroughs will come forth continually. Acknowledgment This work was financially supported by the National Natural Science Foundation of China (Nos. 21504053, 21661162001, 21673139, 51690151, 51473093), and the Program of Shanghai Medical Professionals Across Subject Funds (YG2016MS74). References [1] K. Nagapudi, W.T. Brinkman, B.S. Thomas, et al., Biomaterials 26 (2005) 4695-4706. [2] E.R. Wright, R.A. McMillan, A. Cooper, R.P. Apkarian, V.P. Conticello, Adv. Funct. Mater. 12 (2002) 149-154. [3] F.S. Bates, G.H. Fredrickson, Annu. Rev. Phys. Chem. 41 (1990) 525-557. [4] E.K. Lin, A.P. Gast, Macromolecules 29 (1996) 4432-4441. [5] Y. Seo, T. Kang, H.J. Choi, J. Cho, J. Phys. Chem. C 111 (2007) 5474-5480. [6] R. Banerjee, D. Dhara, Langmuir 30 (2014) 4137-4146. [7] A. Castro, P. Ferreira, P.M. Vilarinho, J. Phys. Chem. C 120 (2016) 10961-10967. [8] O.E. Gould, H. Qiu, D.J. Lunn, et al., Nat. Commun. 6 (2015) 10009. [9] C.K. Jeong, K.M. Baek, S. Niu, Nano Lett. 14 (2014) 7031-7038. [10] C. Shen, Y.H. Lee, Y.P. Lee, React. Funct. Polym. 108 (2016) 94-102. [11] F.E. Alemdaroglu, N.C. Alemdaroglu, P. Langguth, A. Herrmann, Macromol. Rapid Commun. 29 (2008) 326-329. [12] F.E. Alemdaroglu, N.C. Alemdaroglu, P. Langguth, A. Herrmann, Adv. Mater. 20 (2008) 899-902. [13] F.E. Alemdaroglu, J. Wang, M. Börsch, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 47 (2008) 974-976. [14] M.S. Ayaz, M. Kwak, F.E. Alemdaroglu, et al., Chem. Commun. 47 (2011) 2243-2245. [15] R.J. Banga, B. Meckes, S.P. Narayan, et al., J. Am. Chem. Soc. 139 (2017) 4278-4281. [16] M.P. Chien, A.M. Rush, M.P. Thompson, N.C. Gianneschi, Angew. Chem. Int. Ed. 49 (2010) 5076-5080. [17] N. Cottenye, M.I. Syga, S. Nosov, et al., Chem. Commun. 48 (2012) 2615-2617. [18] P. Karimi, K.O. Peters, K. Bidad, P.T. Strickland, Eur. J. Epidemiol. 30 (2015) 91-101. [19] C.J. Kim, X. Hu, S.J. Park, J. Am. Chem. Soc. 138 (2016) 14941-14947. [20] M. Kwak, A. Herrmann, Chem. Soc. Rev. 40 (2011) 5745-5755. [21] H. Liu, Z. Zhu, H. Kang, et al., Chem. Eur. J. 16 (2010) 3791-3797. [22] Q. Luo, Z. Shi, Y. Zhang, et al., J. Am. Chem. Soc. 138 (2016) 10157-10162. [23] E.D. Mentovich, K. Livanov, D.K. Prusty, M. Sowwan, S. Richter, J. Nanobiotechnol. 10 (2012) 21. [24] M. Sowwan, M. Faroun, E. Mentovich, et al., Macromol. Rapid Commun. 31 (2010) 1242-1246. [25] A. Tanaka, Y. Matsuo, Y. Hashimoto, K. Ijiro, Chem. Commun. (2008) 4270-4272. [26] K. Zhang, H. Miao, D. Chen, J. Am. Chem. Soc. 136 (2014) 15933-15941. [27] L. Zhang, A. Eisenberg, Science 268 (1995) 1728-1731. [28] N. Kanayama, H. Shibata, A. Kimura, et al., Biomacromolecules 10 (2009) 805-813. [29] K. Tanabe, T. Asada, S.I. Nishimoto, Biorg. Med. Chem. Lett. 22 (2012) 7045-7047. [30] Z. Li, Y. Zhang, P. Fullhart, C.A. Mirkin, Nano Lett. 4 (2004) 1055-1058. [31] R. Dahm, Dev. Biol. 278 (2005) 274-288. [32] N.C. Seeman, Nature 421 (2003) 427-431. [33] X. Wu, C. Wu, C. Zhang, Chin. J. Polym. Sci. 35 (2017) 1-24. [34] X. Wu, C. Wu, F. Ding, et al., Chin. Chem. Lett. 28 (2017) 851-856. [35] J.Z. Shi, H.Y. Jia, D.S. Liu, Acta Polym. Sin. (2017) 135-142. [36] F. Zhang, F. Hong, H. Yan, Nat. Nanotechnol. 12 (2017) 189-190. [37] Y. Ke, L.L. Ong, W.M. Shih, P. Yin, Science 338 (2012) 1177-1183. [38] P.W.K. Rothemund, Nature 440 (2006) 297-302. [39] M. Lemaitre, B. Bayard, B. Lebleu, Proc. Nat. Acad. Sci. U.S.A. 84 (1987) 648-652. [40] A. Agarwal, R.C. Unfer, S.K. Mallapragada, Biomaterials 29 (2008) 607-617. [41] C. Chen, R.A. Wylie, D. Klinger, L.A. Connal, Chem. Mater. 29 (2017) 1918-1945. [42] M. Bikram, C.H. Ahn, S.Y. Chae, et al., Macromolecules 37 (2004) 1903-1916. [43] M. Kwak, A. Herrmann, Angew. Chem. Int. Ed. 49 (2010) 8574-8587. [44] C. Zhang, L. Hao, C.M. Calabrese, et al., Small 11 (2015) 5360-5368. [45] F.E. Alemdaroglu, K. Ding, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 45 (2006) 4206-4210. [46] M. Oishi, Y. Nagasaki, K. Itaka, N. Nishiyama, K. Kataoka, J. Am. Chem. Soc. 127 (2005) 1624-1625. [47] T. Schnitzler, A. Herrmann, Acc. Chem. Res. 45 (2012) 1419-1430. [48] A. Hernandez-Garcia, N.A. Estrich, M.W.T. Werten, et al., ACS Nano 11 (2017) 144-152. [49] Y. Shao, H. Jia, T. Cao, D. Liu, Acc. Chem. Res. 50 (2017) 659-668. [50] Y. Vyborna, M. Vybornyi, R. Häner, Bioconj. Chem. 27 (2016) 2755-2761. [51] H. Yoshida, Y. Goto, R. Akahori, et al., Nanoscale 8 (2016) 18270-18276. [52] H. Yu, D.T. Alexander, U. Aschauer, R. Häner, Angew. Chem. Int. Ed. 129 (2017) 5122-5126. [53] L. An, L. Liu, S. Wang, Biomacromolecules 10 (2008) 454-457. [54] M. Oishi, T. Hayama, Y. Akiyama, et al., Biomacromolecules 6 (2005) 2449-2454.
[55] C. Li, P. Chen, Y. Shao, et al., Small 11 (2015) 1138-1143. [56] K. Lee, L.K. Povlich, J. Kim, Adv. Funct. Mater. 17 (2007) 2580-2587. [57] Y.G. Takei, T. Aoki, K. Sanui, et al., Bioconj. Chem. 4 (1993) 42-46. [58] P.M. Gramlich, C.T. Wirges, A. Manetto, T. Carell, Angew. Chem. Int. Ed. 47 (2008) 8350-8358. [59] K. Isoda, N. Kanayama, D. Miyamoto, T. Takarada, M. Maeda, React. Funct. Polym. 71 (2011) 367-371. [60] K. Liu, L. Zheng, Q. Liu, et al., J. Am. Chem. Soc. 136 (2014) 14255-14262. [61] K.J. Watson, S.J. Park, J.H. Im, S.T. Nguyen, C.A. Mirkin, J. Am. Chem. Soc. 123 (2001) 5592-5593. [62] C.J. Yang, M. Pinto, K. Schanze, W. Tan, Angew. Chem. Int. Ed. 44 (2005) 2572-2576. [63] X. Pan, S. Lathwal, S. Mack, et al., Angew. Chem. Int. Ed. 56 (2017) 2740-2743. [64] F.E. Alemdaroglu, W. Zhuang, L. Zöphel, et al., Nano Lett. 9 (2009) 3658-3662. [65] K. Ding, F.E. Alemdaroglu, M. Börsch, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 46 (2007) 1172-1175. [66] A.C. Kamps, M.H.M. Cativo, X.J. Chen, S.J. Park, Macromolecules 47 (2014) 3720-3726. [67] Y. Vyborna, M. Vybornyi, A.V. Rudnev, R. Häner, Angew. Chem. Int. Ed. 54 (2015) 7934-7938. [68] A. Hernandez-Garcia, M.W. Werten, M.C. Stuart, F.A. de Wolf, R. de Vries, Small 8 (2012) 3491-3501. [69] D. McIlroy, B. Barteau, J. Cany, et al., Mol. Ther. 17 (2009) 1473-1481. [70] C.K. McLaughlin, G.D. Hamblin, K.D. Hänni, et al., J. Am. Chem. Soc. 134 (2012) 4280-4286. [71] C.J. Serpell, T.G. Edwardson, P. Chidchob, K.M. Carneiro, H.F. Sleiman, J. Am. Chem. Soc. 136 (2014) 15767-15774. [72] T.R. Wilks, J. Bath, J.W. de Vries, et al., ACS Nano 7 (2013) 8561-8572. [73] A.M. Rush, M.P. Thompson, E.T. Tatro, N.C. Gianneschi, ACS Nano 7 (2013) 1379-1387. [74] C.J. Leumann, Biorg. Med. Chem. 10 (2002) 841-854. [75] A. Eschenmoser, CHIMIA Int. J. Chem. 59 (2005) 836-850. [76] C. Schatz, S. Lecommandoux, Macromol. Rapid Commun. 31 (2010) 1664-1684. [77] F.E. Alemdaroglu, A. Herrmann, Org. Biomol. Chem. 5 (2007) 1311-1320. [78] X. Tan, B.B. Li, X. Lu, et al., J. Am. Chem. Soc. 137 (2015) 6112-6115. [79] A. Rodríguez-Pulido, A.I. Kondrachuk, D.K. Prusty, et al., Angew. Chem. Int. Ed. 52 (2013) 1008-1012. [80] F. Huang, M. You, T. Chen, et al., Chem. Commun. 50 (2014) 3103-3105. [81] C. Li, A. Faulkner-Jones, A.R. Dun, et al., Angew. Chem. Int. Ed. 54 (2015) 3957-3961. [82] X. Xiong, C. Wu, C. Zhou, et al., Macromol. Rapid Commun. 34 (2013) 1271-1283. [83] M. Kwak, J. Gao, D.K. Prusty, et al., Angew. Chem. Int. Ed. 50 (2011) 3206-3210. [84] J.H. Kim, J.H. Smit, D.K. Prusty, et al., J. Nanosci. Nanotechnol. 17 (2017) 5175-5180. [85] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, J. Control. Release 65 (2000) 271-284. [86] P.K. Dutta, R. Varghese, J. Nangreave, et al., J. Am. Chem. Soc. 133 (2011) 11985-11993. [87] C. Holzhauser, M.M. Rubner, H.A. Wagenknecht, Photochem. Photobiol. Sci. 12 (2013) 722-724.
Profiles of Corresponding Authors Quanbing Mou completed his BSc degree in Polymer Materials and Engineering from Sichuan University in 2012. Then he strated to pursue his PhD degree under the supervision of Prof. Deyue Yan, Prof. Xinyuan Zhu, and Prof. Chuan Zhang in the School of Chemistry and Chemical Engineering at Shanghai Jiao Tong University. Currently, he is working on the design and synthesis of functional nucleic acid materials, as well as their application in biomedical fields.
Chuan Zhang got his bachelor and master degree of Chemistry at Tsinghua University. After that, he continued his PhD study at Purdue University and obtained the PhD degree in Chemistry in 2011 under supervision of Prof. Chengde Mao. Then he received the postdoctoral training in the group of Prof. Chad A. Mirkin at Northwestern University, USA. He joined the School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University as a tenure-track Associate Professor in 2014. His main research interests focus on DNA supramolecular chemistry, DNA-based nanomaterials for biomedical applications, and cell-material interactions. He has previously received the M. G. Mellon Award in 2010, Young Scholar of Thousand Talent Program, and “Qiu Shi” Outstanding Young Scholar Award in 2014.
S1001-8417(17)30307-8 http://dx.doi.org/10.1016/j.cclet.2017.08.022 CCLET 4171
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Please cite this article as: Gaifang Pan, Xin Jin, Quanbing Mou, Chuan Zhang, Recent progress on DNA block copolymer, Chinese Chemical Lettershttp://dx.doi.org/10.1016/j.cclet.2017.08.022 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Review
Recent progress on DNA block copolymer Gaifang Pan1, Xin Jin1, Quanbing Mou*, Chuan Zhang* School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai 200240, China
Corresponding authors. E-mail addresses: [email protected] (Q. Mou), [email protected] (C. Zhang). 1
These authors contributed equally to this work.
Graphical Abstract
Organic polymers are combined with DNA resulting DNA block copolymers (DBCs) that can simultaneously show the properties of the polymer and DNA. We will discuss some examples of recent developments in the syntheses, structure manipulations, and applications of DBCs.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
DNA has gained great attention because of its unique structure, excellent molecular recognition property, and biological functions. When married with versatile synthetic polymers, the DNA conjugated polymer hybrids, known as DNA block copolymers (DBCs), have been launched and well developed for the syntheses of new materials and nanostructures with different functions in the past several decades. Compared to conventional synthetic block copolymers, using DNA as a building block provides several advantages over other polymer candidates, such as molecular recognition, programmable self-assembly, biocompatibility, and sequence-encoded information. In this mini-review, recent developments in this area will be summarized and meaningful breakthroughs will be highlighted. We will discuss representative examples of recent progress in the syntheses, structure manipulations, and applications of DBCs.
Keywords: DNA block copolymer Self-assembly Nanostructure Hybrid material Micelle
1. Introduction In polymer science, block copolymers have aroused great interest due to their controllable structures and tailorable properties [15]. Owing to the existence of varied segments in a polymer chain, block copolymers and their assemblies exhibit unique properties that are different from their homopolymer counterparts [6-10]. It is well-known that the properties and assembly behaviors of block copolymer are highly related to the chemical nature of its component monomers, the length of each block, and the ratio of block length. However, conventional block polymers that consist of multitude of synthetic polymer segments are lack of precise molecular weight and ordered primary structures for each block, impeding the precise control over their assembling behaviors. Alternatively, nature synthesizes a large variety of biopolymers day and night, which usually have precise lengths and well-defined structures. To construct more useful block copolymers, integrating a precise biomacromolecule as one building block is a feasible way to synthesize novel block copolymers, which can bring the hybrid structures with new properties.
As one of the most important biomacromolecules, DNA can be particularly designed and conjugated with synthetic polymers to form DNA block polymers, named as DBCs [11-30]. Upon consisting of DNA segments, the DBCs behave in both DNA way and polymer way. Particularly, DNA is famous for its double helix structure and the well-known Watson-Crick base pairing [31]. Besides its biological roles, DNA can also be utilized as a generical polymer for new material synthesis based on its excellent molecular recognition and programmable self-assembly power, which has been witnessed by the fast development of “structural DNA nanotechnology” [32-38]. Thus, introducing the DNA segment into block copolymer will bring the DBCs with many hallmark properties that never exist in conventional block copolymers, including accurate chemical structure segment, specific self-assembly driving force, and molecular recognition, etc. Although the synthesis of the first DBC construct can be traced back to the late 1980s [39], this new class of material receive increasing attention and become a popular candidate for novel nanostructure design and construction particularly in the past two decades [40-42]. In general, by appropriate selecting organic polymer and engineering the DNA sequence, the properties and functions of DBC materials can be well-controlled for designated applications. For instance, conjugating hydrophilic polymer results in water-soluble DBCs, which are widely used for hydrogel formation [43]. In contrast, introducing a hydrophobic polymer into DBCs will generate a block copolymer with amphiphilic feature, which can self-assemble into micellar structures with hydrophobic core inside and hydrophilic DNA corona at the surface, enabling them as ideal carrier for drug delivery [44,45]. Moreover, the functions of DBCs are often contributed from all block segments synergistically. On one hand, plenty of synthetic polymers with unique properties can be selected to design functional DBCs. For example, the polymers that are responsive to stimuli such as pH, temperature, light, or salt concentration changes, can endow the DBCs with corresponding stimuliresponsive properties. On the other hand, DNA segments can also bring the DBCs remarkable functions that are linked to their welldefined primary structures, sequence-encoded biological potentials, and molecular recognitions. Along this direction, DBCs and their assemblies have been widely applied for gene or oligodeoxyribonucleotide (ODN) delivery [44,46]. In addition, DNA blocks can also be used to drive the self-assembly in a controllable and precise way for polymer assembly system, resulting in the rational design of various functional nanostructures [47]. Notably, there are plenty of differences between polymer chains and DNA segments, such as synthetic route, solubility, molecular weight and distribution, topology, and self-assembly behaviors [48-52]. Thus, how to balance these differences and controversy is a key issue in designing DBCs materials. Moreover, the controlled syntheses of sophisticated nanostructures with specific functions is always the centre of undergoing DBC related researches. In this mini review, we will briefly review the researches on DBCs in recent years, hoping to provide academic help and share opinions to whom have interests on this topic. In Section 2, we will simply describe several approaches to prepare DBCs, such as solution coupling, solid coupling, and molecular biology strategy. In Section 3, we will focus on introducing the principles and regulations in DBCs self-assembly and recent advances in the obtained nanostructures. Finally, applications of DBCs in different areas will be summarized, such as nanocarriers for drug delivery, chemical reaction templates, 3D printing materials, and nanoelectronics, which are shown in Section 4. 2. Synthesis of DNA block copolymer (DBCs) 2.1. Solution coupling As a typical macromolecule, DNA has inherent molecular order, specific sequence information, and precise molecular weight. Different from most synthetic macromolecules, all DNA materials are totally hydrophilic. Therefore, the first generation of DBCs is synthesized in aqueous solution through click reaction, Michael addition, disulfide bond formation [47,53-59], etc. For example, as a typical type of hydrophilic polymer, peptides have been grafted to DNA through a copper(I)-catalyzed click reaction [55,58]. Moreover, the Michael addition is another approach for the attachment of ODNs to hydrophilic polymers. In this approach, acrylatefunctionalized polymer moieties and thiol-modified ODNs serve as Michael acceptors and Michael donors, respectively [46,59]. Comparatively, DNA segment can hardly dissolve in most organic solvents, which usually leads to low yields of the coupling reaction with a wide range of hydrophobic polymers. As such, modification strategies mentioned above are almost prohibitive for conjugating DNA strands to hydrophobic polymers and the synthesis of DBCs consisting of hydrophobic polymer blocks remains as a big challenge for a long period. To solve this problem, Herrmann and coworkers introduced a DNA-surfactant complex as a reactive scaffold to increase the solubility of DNA segment in organic solution and then successfully establish the organic-phase coupling strategy for DBC syntheses [60]. This surfactant-assisted synthesis strategy has been verified as an effective approach in coupling the ODN to remarkable range of hydrophobic polymers, including poly (propylene oxide) (PPO), polyisoprene (PI), and polystyrene (PS), etc. For example, the synthesis of the ODN-b-PPO (2.5k) block copolymer in organic solvent following the procedure is depicted in Fig. 1 [60]. Moreover, this strategy can be further extended for producing a series of new brush-type of DNA-grafted homopolymers through direct polymerization, shedding new lights for the access of DBCs with more complex structures and functions [52].
Fig. 1. Scheme of the organic-phase synthesis of functional DNA, and DBCs employing activated esters. Reproduced with permission [60]. Copyright 2014, American Chemical Society.
2.2. Solid-phase coupling Although surfactant-assisted synthesis enables the effective DNA conjugation with hydrophobic polymers, surfactants used in the system are usually difficult to be totally removed, which brings purity and safety concerns to the resulting DBCs. Later, solid phase coupling was developed to synthesize DNA/hydrophobic polymer conjugates with high yield, as well as high purity. In general, the amphiphilic DBCs synthesized through solid-phase coupling were prepared by well-established phosphoramidite chemistry and syringe synthesis technique [61]. Due to the efficient exposure of excess phosphoramidite polymer and the high reproducibility of the solid-phase synthesis, DBCs could be prepared in a fully “in line” automated approach [45], which has significant superiority in comparison to a chemical grafting approach in aqueous solution. The automated DNA synthesizer is employed in the synthesis of functionalized DNA. Terminal functionalization can be integrated into the automated synthesis protocol mostly through phosphoramidite chemistry (Fig. 2). Tan and coworkers developed similar synthetic method for coupling oligonucleotides to conjugated polyelectrolytes [62]. Alternatively, post-synthetic modification may be carried out on the solid support outside of the synthesizer. More recently, Matyjaszewski and coworkers developed another robust way to synthesize DBCs via photochemically mediated atom transfer radical polymerization (photo-ATRP) on a DNA synthesizer. Interestingly, both hydrophobic and hydrophilic monomers could be grafted from DNA to form DBCs [63]. Although many DBCs have been synthesized through solid-phase synthetic routes, it is worth noting that this strategy also has some limitations. For example, solvent selection is taken special care due to solvent-dependent swelling properties of cross-linked polymer resins [45]. Moreover, the overall coupling yield will dramatically decrease when a long DNA strand is going to be synthesized, which impedes the synthesis of DBCs with long DNA blocks. Importantly, functional groups introduced on the building block must be stable against the deprotection conditions.
Fig. 2. Cartoon representation of DNA block hydrophobic polymer through solid-phase synthesis (a) and their assemblies (b and c). Reproduced with permission [30]. Copyright 2004, American Chemical Society.
2.3. Molecular biology techniques In an organism, DNA usually exists as long duplexes to encode the genetic information and nature develops specific proteins to synthesize, cut, and manipulate these gene carriers. To construct the DBCs with a longer DNA block, advanced molecular biology techniques can also be used to synthesize the required DNA segments. Polymerase chain reaction (PCR) as well as enzymatic restriction and ligation are the versatile and general tools for the synthesis and manipulation of DNA chains. Recently, PCR technique has been used to synthesize well-defined DNA block copolymer architectures [64]. Di-block copolymer can be obtained by using one single-stranded DNA block copolymer and one oligonucleotide as primers. When two single-stranded DNA block copolymers and one oligonucleotide are used as primers, a tri-block polymer can be constructed (Fig. 3) [47]. With the help of PCR
technique, complicated DNA block polymer with ultrahigh molecular weight and multi-block copolymers with perfect structural composition could be obtained.
Fig. 3. Schematic representation of the build-up of DBCs by using PCR strategy. Reproduced with permission [47]. Copyright 2012, American Chemical Society.
Compared with the PCR approach, it is also possible for enzymatic restriction and ligation to produce the extended DBCs with extremely high molecular weight (~ three million Daltons). By utilizing the DNA restriction enzyme, three double stranded DNA segments with different lengths were synthesized [64]. Then, DBCs with controllable DNA length were synthesized in a one-pot method, through simple mixing and incubation with T4 DNA ligation enzyme (Fig. 4) [64]. Different from chemical coupling strategies mentioned above, this strategy has greatly broadened a wide range of synthetic approaches to construct the DBCs, in which long DNA segments may be equipped with unique and accurate chain information, paving a new avenue for the design and synthesis of DBC-based functional materials.
Fig. 4. Schematic representation of enzymatic restriction and ligation to synthesize DBCs. Reproduced with permission [47]. Copyright 2012, American Chemical Society.
3. DBCs self-assembly and morphology control Owing to consisting of multitude components, the self-assembly behaviors of DBCs are attractive where supramolecular assembly can occur either based on molecular recognition of DNA segments or amphiphilic/electronic interactions in polymer segments. In particular, DNA segments with precise sequence and primary structure exhibit excellent spatial addressability, which further facilitate supramolecular assembly of DBCs. As such, a wide range of nanostructures with various morphologies and functions have been created in the past two decades and we will enumerate some of the recent cases as below. 3.1. Morphology design and control The shape and size distribution of DBCs can be manipulated by regulating the structure nature of DNA segment or polymer segment. For example, the shape of DBCs micelles could be switched between spherical and rod-like aggregates by changing the length of antisense oligonucleotides and designing the template that encodes the complementary sequence of DBCs corona [65]. Most recently, DBCs have been highlighted for opening new routes to construct more complex nanostructures, such as hollowed vesicles. As shown in Fig. 5, when conjugating the DNA with poly[3-(2,5,8,11-tetraoxatridecanyl)thiophene] (PTOTT) by phosphoramidite chemistry, the resulting amphiphilic DNA-b-PTOTT could assemble into vesicles in aqueous solution where DNA acted as the hydrophilic chain and the polymer aggregated in a tense way through hydrophobic interaction as well as π-π stacking [66]. This work suggested that regulation of polymer property could also effectively control the morphology of DBCs’ assemblies. Furthermore, DNA-b-PTOTT can be used to co-assemble with PEG-b-PTOTT (polyethylene glycol (PEG)). With an appropriate ratio, one-dimensional PTOTT nano-ribbons modified with DNA could be realized. As PTOTT is a good semiconducting polymer, the synthesized one-dimensional ribbon may demonstrate potentials in plastic electronics and flexible devices.
Fig. 5. Schematic depiction of the self-assembly of DNA-b-PTOTT into vesicles. Reproduced with permission from [66]. Copyright 2014, American Chemical Society.
The morphology of nanostructure can be regulated not only by driving force but also by specific thermal treatment during the selfassembly process. One successful example is the supramolecular self-assembly of DBC polymer composed of an oligopyrenotide chain and a DNA segment. The degree of order and tightness of pyrene can be increased by using the nucleation-elongation process, resulting in the formation of helical nano-ribbon. In this system, hydrophobic and stacking interactions are the major driving force for pyrene aggregation and elongation, while multi-step thermal treatments at different temperature can force pyrene tensely to be aligned and self-assembled, tuning the lengths of nanoribbons ranging from 50 nm to 500 nm. Importantly, DNA segments distributed around the nano-ribbon still keep their functions (Fig. 6) [67].
Fig. 6. Formation of helical nano-ribbons through nucleation–elongation process of DBCs. Reproduced with permission from [67]. Copyright 2015, WileyVCH.
3.2. Hierarchical and hyper-dimension nanostructures The dimension of nanostructure has not been deeply discussed in other self-assembly systems. In DBCs systems, however, it is feasible to form hierarchical diverse dimensional assemblies due to the existence of multitude driving forces during the self-assembly [68,69]. Indeed, the unique self-recognition properties of DNA allow the DBCs to form hyper-dimensional nanostructures with amazing sophisticated and complex structure, which are not easy to be realized by other means. In this field, Sleiman and co-workers recently developed a DBC by covalently attaching three polymer chains to a DNA strand via ring-opening metathesis polymerization. DNA segments with specific designed sequences can assembled into well-defined DNA nanocage and spontaneously drag tri-block polymer attach to the desired sites on the DNA nanostructure. Importantly, the number and position of the attached polymers could be feasibly regulated (Fig. 7) [70], allowing the polymer-coated DNA cages more resistant to the nuclease compared to those of uncoated DNA structures. Furthermore, this well-defined 3D-DNA “frame” can be used as building blocks to create hyper-dimensional core-shell hybrid assemblies. For instance, by varying the position and multiplicity of the hydrophobic precision polymers on the DNA nanocage, So-Jung and his coworkers further assembled these polymer-addressable 3D DNA cages into highly ordered superstructures. With the tunable geometry of polymer-attached DNA cage units, a library of larger, functional DNA nanostructures could be constructed in an orthogonal assembly manner [71]. This achievement is the first exploration of tuning the interface of precision polymers and DNA nanostructures for constructing hierarchical DBC superstructures. And it could be expected that more exciting and functional structures can be expected to arise from this method.
Fig. 7. Schematic representations of organizing DNA-polymer conjugate onto 3D DNA cubes scaffold. Reproduced with permission [70]. Copyright 2012, American Chemical Society.
Similar to traditional hydrophobic polymers, responsive polymers can also be used as the driving force for secondary selfassembly to form hyper-dimensional nanostructure. Sleiman and his coworkers chose the typical temperature responsive polymer poly(N-isoproylacrylamide) (poly(NIPAM)) as a block to regulate the self-assembly behavior of DBC. At the temperature below the lower critical solution temperature (LCST), poly(NIPAM)-block-DNA can dissolve in the aqueous solution and assemble into a tetrahedron with polymer tails outside. Upon the temperature is higher than the LCST, poly(NIPAM) segments turn into hydrophobic and drive the polymer-DNA cages to form micellar superstructure with tetrahedrons on the surface (Fig. 8) [72]. Acting as the secondary well-defined nanostructure as well as the stabilizers for poly(NIPAM) micelles, DNA tetrahedrons may be further engineered with functional moieties and bring the thermal-responsive superstructure with new features.
Fig. 8. Schematic representations of synthesizing polymer-DNA tetrahedron conjugate and temperature-induced formation of micellar superstructure from poly(NIPAM) attached DNA tetrahedron. Reproduced with permission [72]. Copyright 2013, American Chemical Society.
4. Applications Natural nucleic acids are easily to be hydrolyzed through enzymatic degradation in biological environment, which greatly limits their practical applications for in vivo detection and therapeutic purposes. To solve the problem, DNA analogues have been designed and synthesized with unpredictable off-target effects [73], or with precluding advantageous interactions with key cellular machinery [25,74] which is capable of enzyme-resistance [75]. In a typical DBC assembly, DNA usually acts as the polar head group of DBCs, while polymer block acts as the basic skeleton. Previous studies found that dense packing of DNA in the micelle corona could be achieved through regulation of the polymer segment, with which nuclease cannot reach nucleic acids resulting in a relatively “safe” surrounding from enzymatic degradation during the blood circulation (Fig. 9) [73]. Moreover, the biodegradability and biocompatibility of DNA make them attractive for biomedical applications [76,77]. Specifically, these biodegradable DBCs can internalize into the cells more efficiently than the pristine synthetic oligonucleotides [77]. Thus, DBC-based assemblies capable of enzyme-resistance were widely used in gene regulation, drug delivery, 3D printing, and nanoelectronics, etc.
Fig. 9. Schematic representation of nuclease resistance of DNA-polymer amphiphile nanoparticles. Reproduced with permission [73]. Copyright 2013, American Chemical Society.
4.1. Gene regulation
The utility of DNA in biological application develops rather fast in recent years. Especially, some de novo nanostructures such as spherical nucleic acids (SNAs) exhibit a variety of novel properties that are substantively different from their linear nucleic acid counterparts, making them attractive for intracellular applications. As we know, DNA can act as both delivery material and sequence-dependent therapeutic agents. Thus, involving polymer micelle structures with a dense layer of therapeutic nucleic acids for intracellular gene regulation will be fascinating. For instance, recently we developed a micelle-SNA derived from the DNA brush block copolymer (DBBC). With high dense layer of nucleic acids on its surface, DBBC-based SNA can internalize into the cells more effectively compared to that of the linear DBC assembly even without the use of transfection agents. By designing the DNA to be anti-EGFP antisense sequence, DBBC-based SNA with good biocompatibility and biodegradability show effective target gene knockdown in vitro (Fig. 10) [44]. This DBC-based approach can be extended to deliver various nucleic acid-based therapeutics.
Fig. 10. The synthesis of DNA grafted block copolymer-based micelle-SNAs (a) and gene regulation by DBBC-based micelle-SNAs (b). Reproduced with permission [44]. Copyright 2015, Wiley-VCH.
4.2. Drug delivery Apart from gene therapy, a variety of DNA-based systems have been constructed for cancer therapy, biosensing, and detection. Here we will first introduce a typical strategy of DNA-based delivery system with DNA conjugated to chemotherapeutics for cancer therapy. A library of hydrophobic drugs can be attached to DNA segment, and the amphiphilicity of the DBCs conjugates allows them to assemble into micellar nanostructures for drug delivery. This strategy is feasible with great diversities. However, one major problem is the drug release issue. To overcome this barrier, as shown in Fig. 11, stimuli-responsive breakable linkage was introduced into DNA-drug conjugates [78]. DNA-camptochecin (CPT) was synthesized as a drug-cored nucleic acid nanostructure containing hydrophobic CPT as chemotherapeutic agents. Upon UV light (365 nm), the 2-nitrobenzyl group can be cleaved, releasing the DNA segment from the nanostructure and leaving a decapped self-immolative drug core for further treatment. This approach has provided a feasible method to control drug release behavior. Similarly, Herrmann and coworkers developed a novel function of DNA-lipid vesicle system for selective cargo release from lipid vesicles based on amphiphilic DBCs and the hybridization of photosensitizer units. Thus, the delivery system could release cargo through physicochemical responses to light irradiation [79]. What’s more, DBC-based hybrid nanoparticles can be used to co-deliver DOX and PTX with high specificity and efficiency [80].
Fig. 11. Schematics of the DNA-drug nanostructures assembled from photolabile DNA-drug amphiphiles. Reproduced with permission from [78]. Copyright 2015, American Chemical Society.
4.3. 3D printing 3D printing has drawn great attention in tissue engineering as a powerful fabrication method to design and create tissue-like structures. Particularly for 3D bioprinting, biodegradable and biocompatible scaffold materials, such as hydrogel [82], are critical to
be used as the bio-inks. Liu and coworkers reported the rapid formation of a supramolecular polypeptide-DNA hydrogel as the bioink, which was subsequently used for in situ multilayer 3D bioprinting (Fig. 12) [81]. The printed hydrogels possess excellent healing and can keep their shapes up to the millimeter scale without collapse. Such a biocompatible and biodegradable hydrogel is a new promising printable biomaterial for the fabrication of complex three-dimensional tissue-like constructs for tissue engineering.
Fig. 12. 3D bioprinting of polypeptide-DNA hydrogels with AtT-20 cells. Reproduced with permission [81]. Copyright 2015, Wiley-VCH.
4.4. Nanoelectronics Synthetic DNA tends to self-assemble into nanoparticles with high order and multi-hole structures, which makes DBCs a popular choice for conducting polymer templates and nanoelectronics applications. After complex with SWNTs, an amphiphilic DBC consisting of poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO) block and 22mer single-stranded OND was applied to help SWNTs locate on the substrate (Fig. 13) [83]. This might be the first success for site-specifically immobilizing individual carbon nanotube in a programmed and large-scale way. Recently, Herrmann and coworkers took advantage of the interactions for the self-assembly of field-effect transistors from semiconducting single-walled carbon nanotubes selectively dispersed by DBCs and anchored to the electrodes through DNA hybridization. These transistors could sensitively detect the hybridization of complementary target DNA strands through transduction of the chemical recognition event into electrical doping, yielding an analyte sensitivity of 10 fmol/L. Such ultra-sensitive electrical-based detection offered a fantastic way to nucleic acids diagnostics with no need for DNA amplification [84].
Fig. 13. Complex DBCs with SWNTs and its application in nanoelectronics. Reproduced with permission [83]. Copyright 2011, Wiley-VCH.
5. Conclusion As a novel hybrid material, DBCs behave in a higher level of controllability than the other kinds of block copolymers, due to DNA’s unique self-assembly property. Through molecular recognition powered by the DNA segments, novel architectures become assessable in a DNA-directed self-assembly manner. Compared to assemblies from synthetic polymers only, nanostructures assembled by DBCs are of high tunability, hyper-dimension, and multi-functions. Therefore, the potential applications of these unique materials and their assemblies are located in a broad range of areas, such as drug delivery, complex nanostructure fabrication,
nanosized sensors, and high performance nanoelectronics [85-87]. With the fast development of new coupling techniques that can effectively conjugate the DNA with hydrophilic and hydrophobic polymers, we believe more DBCs with a broad range of properties and functions will be synthesized for more high-tech applications. As highly tunable and functional materials, the segments in DBCs can be further engineered in future. For instance, organic polymer with stimuli-responsive properties can be expected for constructing smart nanomaterials for bionanotechnology. Meanwhile, a broad range of chemical and biological techniques can be used for the modification of DNA blocks, which will give access to new materials with more biological functions. Nevertheless, some challenges remain in this promising field. For instance, there is lack of a universal approach to fabricate different types of DBCs even though various synthetic strategies have been established as mentioned above. In addition, the high local DNA concentration of DBC assemblies might cause immune response for in vivo applications, which may be overcome through de novo design of DNA sequences. Despite these challenges, great opportunities still exist for researchers in this emerging area and we believe more breakthroughs will come forth continually. Acknowledgment This work was financially supported by the National Natural Science Foundation of China (Nos. 21504053, 21661162001, 21673139, 51690151, 51473093), and the Program of Shanghai Medical Professionals Across Subject Funds (YG2016MS74). References [1] K. Nagapudi, W.T. Brinkman, B.S. Thomas, et al., Biomaterials 26 (2005) 4695-4706. [2] E.R. Wright, R.A. McMillan, A. Cooper, R.P. Apkarian, V.P. Conticello, Adv. Funct. Mater. 12 (2002) 149-154. [3] F.S. Bates, G.H. Fredrickson, Annu. Rev. Phys. Chem. 41 (1990) 525-557. [4] E.K. Lin, A.P. Gast, Macromolecules 29 (1996) 4432-4441. [5] Y. Seo, T. Kang, H.J. Choi, J. Cho, J. Phys. Chem. C 111 (2007) 5474-5480. [6] R. Banerjee, D. Dhara, Langmuir 30 (2014) 4137-4146. [7] A. Castro, P. Ferreira, P.M. Vilarinho, J. Phys. Chem. C 120 (2016) 10961-10967. [8] O.E. Gould, H. Qiu, D.J. Lunn, et al., Nat. Commun. 6 (2015) 10009. [9] C.K. Jeong, K.M. Baek, S. Niu, Nano Lett. 14 (2014) 7031-7038. [10] C. Shen, Y.H. Lee, Y.P. Lee, React. Funct. Polym. 108 (2016) 94-102. [11] F.E. Alemdaroglu, N.C. Alemdaroglu, P. Langguth, A. Herrmann, Macromol. Rapid Commun. 29 (2008) 326-329. [12] F.E. Alemdaroglu, N.C. Alemdaroglu, P. Langguth, A. Herrmann, Adv. Mater. 20 (2008) 899-902. [13] F.E. Alemdaroglu, J. Wang, M. Börsch, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 47 (2008) 974-976. [14] M.S. Ayaz, M. Kwak, F.E. Alemdaroglu, et al., Chem. Commun. 47 (2011) 2243-2245. [15] R.J. Banga, B. Meckes, S.P. Narayan, et al., J. Am. Chem. Soc. 139 (2017) 4278-4281. [16] M.P. Chien, A.M. Rush, M.P. Thompson, N.C. Gianneschi, Angew. Chem. Int. Ed. 49 (2010) 5076-5080. [17] N. Cottenye, M.I. Syga, S. Nosov, et al., Chem. Commun. 48 (2012) 2615-2617. [18] P. Karimi, K.O. Peters, K. Bidad, P.T. Strickland, Eur. J. Epidemiol. 30 (2015) 91-101. [19] C.J. Kim, X. Hu, S.J. Park, J. Am. Chem. Soc. 138 (2016) 14941-14947. [20] M. Kwak, A. Herrmann, Chem. Soc. Rev. 40 (2011) 5745-5755. [21] H. Liu, Z. Zhu, H. Kang, et al., Chem. Eur. J. 16 (2010) 3791-3797. [22] Q. Luo, Z. Shi, Y. Zhang, et al., J. Am. Chem. Soc. 138 (2016) 10157-10162. [23] E.D. Mentovich, K. Livanov, D.K. Prusty, M. Sowwan, S. Richter, J. Nanobiotechnol. 10 (2012) 21. [24] M. Sowwan, M. Faroun, E. Mentovich, et al., Macromol. Rapid Commun. 31 (2010) 1242-1246. [25] A. Tanaka, Y. Matsuo, Y. Hashimoto, K. Ijiro, Chem. Commun. (2008) 4270-4272. [26] K. Zhang, H. Miao, D. Chen, J. Am. Chem. Soc. 136 (2014) 15933-15941. [27] L. Zhang, A. Eisenberg, Science 268 (1995) 1728-1731. [28] N. Kanayama, H. Shibata, A. Kimura, et al., Biomacromolecules 10 (2009) 805-813. [29] K. Tanabe, T. Asada, S.I. Nishimoto, Biorg. Med. Chem. Lett. 22 (2012) 7045-7047. [30] Z. Li, Y. Zhang, P. Fullhart, C.A. Mirkin, Nano Lett. 4 (2004) 1055-1058. [31] R. Dahm, Dev. Biol. 278 (2005) 274-288. [32] N.C. Seeman, Nature 421 (2003) 427-431. [33] X. Wu, C. Wu, C. Zhang, Chin. J. Polym. Sci. 35 (2017) 1-24. [34] X. Wu, C. Wu, F. Ding, et al., Chin. Chem. Lett. 28 (2017) 851-856. [35] J.Z. Shi, H.Y. Jia, D.S. Liu, Acta Polym. Sin. (2017) 135-142. [36] F. Zhang, F. Hong, H. Yan, Nat. Nanotechnol. 12 (2017) 189-190. [37] Y. Ke, L.L. Ong, W.M. Shih, P. Yin, Science 338 (2012) 1177-1183. [38] P.W.K. Rothemund, Nature 440 (2006) 297-302. [39] M. Lemaitre, B. Bayard, B. Lebleu, Proc. Nat. Acad. Sci. U.S.A. 84 (1987) 648-652. [40] A. Agarwal, R.C. Unfer, S.K. Mallapragada, Biomaterials 29 (2008) 607-617. [41] C. Chen, R.A. Wylie, D. Klinger, L.A. Connal, Chem. Mater. 29 (2017) 1918-1945. [42] M. Bikram, C.H. Ahn, S.Y. Chae, et al., Macromolecules 37 (2004) 1903-1916. [43] M. Kwak, A. Herrmann, Angew. Chem. Int. Ed. 49 (2010) 8574-8587. [44] C. Zhang, L. Hao, C.M. Calabrese, et al., Small 11 (2015) 5360-5368. [45] F.E. Alemdaroglu, K. Ding, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 45 (2006) 4206-4210. [46] M. Oishi, Y. Nagasaki, K. Itaka, N. Nishiyama, K. Kataoka, J. Am. Chem. Soc. 127 (2005) 1624-1625. [47] T. Schnitzler, A. Herrmann, Acc. Chem. Res. 45 (2012) 1419-1430. [48] A. Hernandez-Garcia, N.A. Estrich, M.W.T. Werten, et al., ACS Nano 11 (2017) 144-152. [49] Y. Shao, H. Jia, T. Cao, D. Liu, Acc. Chem. Res. 50 (2017) 659-668. [50] Y. Vyborna, M. Vybornyi, R. Häner, Bioconj. Chem. 27 (2016) 2755-2761. [51] H. Yoshida, Y. Goto, R. Akahori, et al., Nanoscale 8 (2016) 18270-18276. [52] H. Yu, D.T. Alexander, U. Aschauer, R. Häner, Angew. Chem. Int. Ed. 129 (2017) 5122-5126. [53] L. An, L. Liu, S. Wang, Biomacromolecules 10 (2008) 454-457. [54] M. Oishi, T. Hayama, Y. Akiyama, et al., Biomacromolecules 6 (2005) 2449-2454.
[55] C. Li, P. Chen, Y. Shao, et al., Small 11 (2015) 1138-1143. [56] K. Lee, L.K. Povlich, J. Kim, Adv. Funct. Mater. 17 (2007) 2580-2587. [57] Y.G. Takei, T. Aoki, K. Sanui, et al., Bioconj. Chem. 4 (1993) 42-46. [58] P.M. Gramlich, C.T. Wirges, A. Manetto, T. Carell, Angew. Chem. Int. Ed. 47 (2008) 8350-8358. [59] K. Isoda, N. Kanayama, D. Miyamoto, T. Takarada, M. Maeda, React. Funct. Polym. 71 (2011) 367-371. [60] K. Liu, L. Zheng, Q. Liu, et al., J. Am. Chem. Soc. 136 (2014) 14255-14262. [61] K.J. Watson, S.J. Park, J.H. Im, S.T. Nguyen, C.A. Mirkin, J. Am. Chem. Soc. 123 (2001) 5592-5593. [62] C.J. Yang, M. Pinto, K. Schanze, W. Tan, Angew. Chem. Int. Ed. 44 (2005) 2572-2576. [63] X. Pan, S. Lathwal, S. Mack, et al., Angew. Chem. Int. Ed. 56 (2017) 2740-2743. [64] F.E. Alemdaroglu, W. Zhuang, L. Zöphel, et al., Nano Lett. 9 (2009) 3658-3662. [65] K. Ding, F.E. Alemdaroglu, M. Börsch, R. Berger, A. Herrmann, Angew. Chem. Int. Ed. 46 (2007) 1172-1175. [66] A.C. Kamps, M.H.M. Cativo, X.J. Chen, S.J. Park, Macromolecules 47 (2014) 3720-3726. [67] Y. Vyborna, M. Vybornyi, A.V. Rudnev, R. Häner, Angew. Chem. Int. Ed. 54 (2015) 7934-7938. [68] A. Hernandez-Garcia, M.W. Werten, M.C. Stuart, F.A. de Wolf, R. de Vries, Small 8 (2012) 3491-3501. [69] D. McIlroy, B. Barteau, J. Cany, et al., Mol. Ther. 17 (2009) 1473-1481. [70] C.K. McLaughlin, G.D. Hamblin, K.D. Hänni, et al., J. Am. Chem. Soc. 134 (2012) 4280-4286. [71] C.J. Serpell, T.G. Edwardson, P. Chidchob, K.M. Carneiro, H.F. Sleiman, J. Am. Chem. Soc. 136 (2014) 15767-15774. [72] T.R. Wilks, J. Bath, J.W. de Vries, et al., ACS Nano 7 (2013) 8561-8572. [73] A.M. Rush, M.P. Thompson, E.T. Tatro, N.C. Gianneschi, ACS Nano 7 (2013) 1379-1387. [74] C.J. Leumann, Biorg. Med. Chem. 10 (2002) 841-854. [75] A. Eschenmoser, CHIMIA Int. J. Chem. 59 (2005) 836-850. [76] C. Schatz, S. Lecommandoux, Macromol. Rapid Commun. 31 (2010) 1664-1684. [77] F.E. Alemdaroglu, A. Herrmann, Org. Biomol. Chem. 5 (2007) 1311-1320. [78] X. Tan, B.B. Li, X. Lu, et al., J. Am. Chem. Soc. 137 (2015) 6112-6115. [79] A. Rodríguez-Pulido, A.I. Kondrachuk, D.K. Prusty, et al., Angew. Chem. Int. Ed. 52 (2013) 1008-1012. [80] F. Huang, M. You, T. Chen, et al., Chem. Commun. 50 (2014) 3103-3105. [81] C. Li, A. Faulkner-Jones, A.R. Dun, et al., Angew. Chem. Int. Ed. 54 (2015) 3957-3961. [82] X. Xiong, C. Wu, C. Zhou, et al., Macromol. Rapid Commun. 34 (2013) 1271-1283. [83] M. Kwak, J. Gao, D.K. Prusty, et al., Angew. Chem. Int. Ed. 50 (2011) 3206-3210. [84] J.H. Kim, J.H. Smit, D.K. Prusty, et al., J. Nanosci. Nanotechnol. 17 (2017) 5175-5180. [85] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, J. Control. Release 65 (2000) 271-284. [86] P.K. Dutta, R. Varghese, J. Nangreave, et al., J. Am. Chem. Soc. 133 (2011) 11985-11993. [87] C. Holzhauser, M.M. Rubner, H.A. Wagenknecht, Photochem. Photobiol. Sci. 12 (2013) 722-724.
Profiles of Corresponding Authors Quanbing Mou completed his BSc degree in Polymer Materials and Engineering from Sichuan University in 2012. Then he strated to pursue his PhD degree under the supervision of Prof. Deyue Yan, Prof. Xinyuan Zhu, and Prof. Chuan Zhang in the School of Chemistry and Chemical Engineering at Shanghai Jiao Tong University. Currently, he is working on the design and synthesis of functional nucleic acid materials, as well as their application in biomedical fields.
Chuan Zhang got his bachelor and master degree of Chemistry at Tsinghua University. After that, he continued his PhD study at Purdue University and obtained the PhD degree in Chemistry in 2011 under supervision of Prof. Chengde Mao. Then he received the postdoctoral training in the group of Prof. Chad A. Mirkin at Northwestern University, USA. He joined the School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University as a tenure-track Associate Professor in 2014. His main research interests focus on DNA supramolecular chemistry, DNA-based nanomaterials for biomedical applications, and cell-material interactions. He has previously received the M. G. Mellon Award in 2010, Young Scholar of Thousand Talent Program, and “Qiu Shi” Outstanding Young Scholar Award in 2014.