Self-Assembly of DNA-Containing Copolymers - Bioconjugate

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Self-assembly of DNA-containing copolymers Fei Jia, Hui Li, Runhua Chen, and Ke Zhang Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.9b00067 • Publication Date (Web): 21 Feb 2019 Downloaded from http://pubs.acs.org on February 23, 2019

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Bioconjugate Chemistry

Self-assembly of DNA-containing copolymers Fei Jia,† Hui Li,‡ Runhua Chen,§* and Ke Zhang†‡§* §College

of Environmental Science and Engineering, Central South University of Forestry and

Technology, Changsha, 410007, China †Department

of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave,

Boston, Massachusetts, 02115, USA ‡Institute

of Chemical Biology and Nanomedicine, College of Chemistry and Chemical

Engineering, Hunan University, Changsha, 410082, China

ABSTRACT: While the solution assembly of amphiphilic copolymers has been studied extensively, the assembly of DNA-containing copolymers is only recently emerging as a promising new area. DNA, a natural hydrophilic biopolymer that is highly predictable in its hybridization characteristics, brings to the field several useful and unique properties including monodispersity, ability to functionalize in a site-specific manner, and programmability with Watson-Crick base pairing. The inclusion of DNA as a segment in the copolymer not only adds to the current knowledge base in block copolymer assembly but also creates new modalities of assembly that have already led to novel and technologically useful structures. In this review, we discuss recent progress in the self-assembly of DNA-containing copolymers, including assemblies driven by hydrophobicity via amphiphilic constructs, programmed assemblies mediated by DNA hybridization, and assemblies involving both of these interactions.

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Introduction One of the ultimate goals of chemistry is to reproduce the programmability, directionality, and precise character of the supramolecular interactions seen in biology with synthetic materials. Mastering such supramolecular assemblies will have a significant impact on a number of fields spanning medical diagnostics and therapeutics, catalysis, energy, data storage, among others.1-4 Block copolymer self-assembly and DNA nanotechnology are two of the better-studied systems towards this goal.5-10 Although substantial progress has been made in these two fields separately, a strategy to synergistically merge them, i.e. to program the ordered assembly of polymer molecules in a predictable fashion using DNA, is still very much in the embryonic stage. The ability to assemble polymer constructs with precise arrangement of individual macromolecules is expected to give rise to a vast range of novel multiscale materials with unique electronic, optical, and biological properties that can be tuned by their dimensions and cooperativity.11, 12 DNA is a particularly powerful tool for the programmable bottom-up assembly of materials. By virtue of the predictability of hybridization, DNA sequence-specific recognition has been used to assemble materials such as noble metal particles,13-16 quantum dots,17,

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materials such as proteins19-21 and polymers.22, 23 In this assembly modality, DNA is used as a functional group-equivalent to tether macromolecular, nanoscopic, or even microscopic building blocks together. Because DNA is highly programmable, one can in principle create a very large numbers of “functional groups” that work orthogonally in one pot. For DNA-polymer conjugates, the challenges include methods to enable directional (as opposed to omnidirectional) assembly, and ability to precisely control the position, density, and orientation of the polymer. Other than being capable of base recognition, DNA is also a hydrophilic, highly negatively charged polyelectrolyte. When covalently incorporated with a hydrophobic polymer, DNA can


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undergo phase separation in an aqueous solution to form the hydrophilic corona surrounding the resulting supramolecular nanostructure. While this behavior is similar to that of other wellstudied amphiphilic copolymers, the DNA component brings to the field new tricks. For example, DNA can be site-specifically functionalized, thanks to advances in solid-phase oligonucleotide synthesis, allowing the polymer to be connected to any position of the DNA, which has an impact on the architecture of the copolymer.24-26 Second, the DNA component of the copolymer can pre-assemble to form a DNA nanostructure, which alters the shape/size of the hydrophilic component and pre-determines the location and orientation of the polymer.27, 28

Figure 1. Modes of assembly for DNA-containing polymers.

In this review, we highlight recent advances in the self-assembly of DNA-containing copolymers, with the exclusion of DNA-polymer hydrogels, as there are already several current reviews on this topic.29-32 We first review the solution self-assembly of amphiphilic DNAcontaining copolymers without requiring DNA base pairing, followed by a discussion on programmable self-assembly with the assistance of base sequence recognition. Last, we will


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address assemblies that take advantage of both polymer-specific interactions and DNA base sequence recognition (Figure 1). Assemblies via polymer hydrophobic interactions Block copolymers are an important class of materials, which consist of two or more polymer segments that are covalent linked. With advances in the ability to manipulate DNA both in the solid phase and the solution phase, DNA block copolymers (DBCs), in which DNA is considered as a polymer block, have become increasingly accessible since the first DBC example, DNA-bpoly(L-lysine), was reported by Lebleu et al. in 1987.33 Although fully hydrophilic DBCs can be effectively synthesized by solution-phase coupling, amphiphilic DBCs are more difficult due to the lack of an appropriate solvent system to solubilize both the DNA and the hydrophobic polymer.34,

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As such, solid-phase syntheses are more popular because the DNA phosphate

backbone and nucleobases are protected and therefore hydrophobic before deprotection, making coupling reactions in organic solvents efficient. A potential drawback of solid-phase synthesis is that the polymer must be able to withstand the basic DNA deprotection conditions. Herrmann et al addressed this problem through the use of a DNA-cationic surfactant complex, which brings the DNA into the organic phase for solution-phase coupling.36 In terms of synthetic methodology, direct ligation of pre-synthesized DNA and polymer,37-45 growth of polymer from a DNA initiator46, 47 or chain-transfer agent,48, 49 and growth of DNA from a free polymer chain as a support,50 have all been demonstrated.


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Figure 2. Hydrophobicity-driven (co)assembly of amphiphilic DBCs. (a) Spherical micelles coassembled from PCL, PEG-b-PCL, and DNA-b-PCL.51 (b) Self-assembly of HE12-b-DNA conjugates generates spherical DNA nanoparticles and nanofibers.52 (c) Self-assembly of Py7-bDNA conjugate into a DNA-grafted supramolecular ribbon. Reproduced with permission from [53]. Copyright 2017, Royal Society of Chemistry.

Owing to the highly hydrophilic and negatively charged nature of the DNA strands, amphiphilic DBCs tend to self-assemble into micelles with a high-density nucleic acid corona and a polymeric core. These nucleic acid nanostructures exhibit several unusual properties that are typical of spherical nucleic acids (SNAs), which include enhanced binding with a complementary sequence, increases in enzymatic stability, and significantly elevated cellular uptake.54-56 These properties make the DBC nanostructures attractive organic materials for biomedical applications. Mirkin et al prepared a polystyrene (PS)-b-DNA DBC by modifying the PS chain-end with a phosphoramidite moiety, allowing it to be used in solid-phase DNA


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synthesis.39 Spherical micelles were observed though nanoprecipitation. Zhang et al expanded upon this work by creating library of PS-b-DNA DBCs with variations in DNA and PS lengths (Cu-catalyzed alkyne-azide click chemistry was used instead), and a pseudo phase diagram was plotted.57 The high glass transition temperature of PS (TG = 95 ºC) makes it difficult for the micelles to reach thermodynamic equilibrium at room temperature, which kinetically traps the assemblies in intermediate morphologies such as rods and branched networks. As temperatures rose above the TG, all rod-like structures obtained through nanoprecipitation transformed into spherical particles. The DBC-based approach has been adopted by several groups to prepare similar spherical DNA micelles with different polymeric cores, for example by Gianneschi58, 59 in the synthesis of a polynorbornene-based conjugate and by Zhang51 and Mirkin41 in the preparation of polycaprolactone (PCL)-cored DNA micelles (Figure 2a). Notably, Sleiman et al prepared DBCs using entirely automated solid-phase DNA synthesis, during which several hydrophobic hexaethylene (HE) spacer units were incorporated consecutively to create the hydrophobic block (Figure 2b).60 The same approach was also adopted by Häner et al to incorporate a string of pyrene units adjacent to the DNA block, and the resulting DBC forms ribbons and networks in an aqueous solution (Figure 2c).53,

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These DBCs carry the distinct advantage of being

molecularly pure and thus more reproducible and uniform in their supramolecular formulations. Interestingly, in the Sleiman study,52 the attachment of a single or two cyanine 3 dyes at or near the distal end of the hydrophobic segment of the DBC completely changes the morphology of the resulting micelle, from spheres to 1-D nanofibers, despite the relatively small size of the dye (~440 Da) compared to that of the overall DBC (~10 kDa), likely via a perturbation of packing modes. These nanofibers have been shown to assemble following a seed-mediated, chain-growth


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mechanism. Such strong influence on assembly by a low molecular weight species was also observed in a study by Alexander et al,63 wherein the hydrophobic interaction of a single cholesterol molecule (~387 Da) attached to the 5’ end of a DNA was able to drive the arrangement of a DNA-poly(ethylene glycol) (PEG) conjugate (8.7 kDa combined) into spherical micelles. This phenomenon is likely highly specific to the hydrophobic moiety used, as the DNA can exert strong intermolecular repulsive interactions through the negative surface charge, often requiring high salt concentrations (especially salts with divalent metal cations) or a large enough hydrophobic interaction to drive assembly. For example, Zhang et al reported that that a DNAcamptothecin (CPT) conjugate with three CPT molecules (1519 Da) formed spherical assemblies in 0.05x phosphate buffered saline (PBS) when the DNA was shorter than ~5 nucleotides.64 With the addition of 2-5 mg MgCl2, much longer DNA strands (longest tested: 20 nucleotides) also assembled into micelles, despite having a rod-like morphology. In a subsequent study, the number of hydrophobic drug molecule (paclitaxel) was increased to 10 through polymerization, and the corresponding DBC was able to form stable micelles even without any salt to screen the charge repulsion due to sufficient micellization enthalpy.65 Beside typical spherical micelles, other morphologies have also been obtained using DBCs. Park et al discovered that a DBC having a semiconducting polymer, poly[3-(2,5,8,11tetraoxatridecanyl)-thiophene] (PTOTT), led to the formation of vesicular structures.66 This unusual morphology was explained by the π-π interaction of the rigid PTOTT block: organizing the conjugate into spherical micelles with a high interfacial curvature would lead to significant packing defects in the micelle core, if one considers the PTOTT polymer as a rigid, rod-like block. When DNA-b-PTOTT is co-assembled with PEG-b-PTOTT, one-dimensional polythiophene nanoribbons were formed. In this case, the DBC fraction is low, and the


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morphology of the assembled structure is dictated by PEG-b-PTOTT, which forms nanoribbons by itself. Sheet-like morphologies were observed by Sleiman et al for the HEn-b-DNA DBCs, when a short DNA (8-mer) and a long hydrophobic chain (12 HE units) were used.52 Of note, the morphologies having been observed with DBCs are far fewer compared to the vast numbers seen with non-DNA block copolymers, which suggests an opportunity for further research. The supramolecular assemblies are oftentimes dynamic if the polymer chains within the core have some degree of mobility, which allows the assembled structure to undergo shape-shifting. Triggers of the shape-shifting process may involve changes in the physical environment of the micelle, such as pH, ionic strength, and temperature, as was the case in the Zhang study involving PS-b-DNA DBCs (vide supra).57 Park et al reported a thermally switchable triblock copolymer, DNA-b-poly(N-isopropylacrylamide) (PNIPAM)-b-poly(methyl acrylate) (PMA).67 At temperatures below the lower critical solution temperature (LCST) of PNIPAM, both the DNA and the PNIPAM blocks are hydrophilic, and the overall hydrophilic/hydrophobic volume ratio favors spherical micelles (Figure 3a). Above the LCST, the PNIPAM block joins PMA to become the hydrophobic core of an increased volume, which reduces the micellar interfacial curvature and transforms the spheres to cylinders. In addition to physical environment changes, covalently or non-covalently altering the structure of the original DBC in the micellar form can also lead to shape-shifting. For instance, Gianneschi used DNAzymes to cleave the DNA strands in a pre-formed spherical DBC micelle, which reduced the length of the DNA and therefore the micellar interfacial curvature, leading to a sphere-to-rod transformation (Figure 3b). Upon relengthening the DNA by hybridization with a longer strand, the micelles returned to the original spherical form.58 Changes in the micelle core can also induce shape-shifting. In the HE-b-DNA DBC study by Sleiman et al (vide supra),52 a photocleavable linker between the cyanine 3 dyes


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and the HE segment was introduced. Upon irradiation, the dye molecules were released, which altered the packing mode of the HE block, transforming the rods to nearly monodisperse spheres, despite non-quantitative photocleavage. To non-covalently induce micelle shape-shifting, the Liu group conjugated an i-motif DNA, which reversibly transitions from a four-stranded structure via protonated cytosine-cytosine base pairing under acidic condition to a random coil conformation under basic condition, to poly(propylene oxide) (PPO).68 The resulting DNA-b-PPO micelles shifted between cylindrical and spherical morphologies by changing pH and annealing (Figure 3c).

Figure 3. Shape-shifting assemblies. (a) Triblock copolymer micelles consisting of DNA-bPNIPAM-b-PMA shift in morphology in response to changes in temperature or DNA length.67 (b) Micelles of a brush-type DNA amphiphile undergoes shape-shifting induced by shortening or


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lengthening the DNA strand. Reproduced with permission from [58]. Copyright 2010, WileyVCH. (c) Reversible shape transformation of DNA-b-PPO copolymers micelles in response to pH. Reproduced with permission from [68]. Copyright 2012, Royal Society of Chemistry.

Although the majority of hydrophobicity-driven assemblies studied thus far consist of linear DBCs, there is an increasing presence of non-linear conjugates in the literature. For example, Liu et al pioneered a class of dendrimer-DNA conjugates.69 In one study, 9- and 18-mer DNA strands were conjugated to poly(benzyl ether) dendrons (G1 through G3) capped with dichlorobenzene, and the resulting amphiphiles robustly formed nanofibers irrespective of the dendron generation and DNA length. Notably, even the G1 conjugate, with a small hydrophobic/hydrophilic weight ratio of 0.079, also formed long nanofibers. Another type of non-linear DNA copolymer involves random grafts of DNA strands on a linear or branched polymer backbone. Although architecturally complex, the DNA-graft copolymers can selfassemble through polymer hydrophobic interactions to form spherical particles similar to linear DBCs, as reported by Tan et al in the case of an aptamer-grafted hyperbranched polymer (Figure 4a).70 The hyperbranched polymer was designed to contain pendant, UV-sensitive o-nitrobenzyl groups, which mask carboxylic acid moieties. When de-masked by UV light, the repulsion of the negatively charged carboxylates causes the disassembly of the nanoparticle into individual polymers and the release of an encapsulated payload (doxorubicin). In additional to spherical structures, anisotropic particles such as rods are also possible. For example, Jiang et al grafted multiple DNA strands onto a poly(propargyl methacrylate) (PPMA) backbone (Figure 4b).71 The resulting conjugate assembled into primary fibers, which then further hierarchically assembled to yield parallelly aligned nanofibers and wrapped multi-stranded nanofibers.


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Figure 4. Non-linear DBCs and their assemblies. (a) Photoresponsive, DNA-grafted hyperbranched polymer for drug delivery. Reproduced with permission from [70]. Copyright 2018, Wiley-VCH. (b) Self-assembly of PPMA-g-DNA, which produces nanofibers. Reproduced with permission from [71]. Copyright 2015, Royal Society of Chemistry.

Assemblies driven by DNA base-pairing In the previous section, DNA serves only as a polyelectrolyte in the self-assembly process without involving base pairing. Next, we review the opposite scenario: assemblies driven mainly by hybridization. One possibility of DNA-mediated assemblies of polymers of this type is to treat DNA as a rigid scaffold, which is used to organize polymer molecules in a site-, orientation-, and number-specific manner. For example, the Sleiman group reported the alignment of polymer nanoparticles on DNA nanotubes via hybridization.72 The nanotube backbone consists of a long, single-stranded DNA, which is prepared by rolling circle amplification, an enzymatic process that can generate a long DNA strand with periodic sequences from a cyclic template. The backbone is connected to triangular DNA rungs to form the nanotubes, which acted as a scaffold, onto which PEG-DNA conjugate nanoparticles can position themselves using sequence-specific hybridization, resulting in uniformly aligned polymer nanoparticles along the DNA nanotube with equal spacing (Figure 5a). Since the polymer nanoparticles were hybridized to the DNA


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nanotube, they can also be easily “erased” using a strand-displacement method, giving the assemblies a “write–erase” property. The same group also reported a series of work about DNA nanocages and their roles in assembling polymer molecules. In one study, four 80-mer singlestrand DNA were used to create a DNA cube with eight single-stranded regions. A star PEGDNA conjugate bearing a complementary DNA sequence was then hybridized to the cage, which allows the arrangement of a precise number of polymers on specific facets of the cube.73 These two studies demonstrate the power of using DNA to achieve long-range ordering of polymers and the ability to control density, number, and orientation.

Figure 5. DNA base pairing as the driving force for assembly. (a) DNA nanotube-guided assembly of DNA-g-PEG aggregates. Reproduced with permission from [72]. Copyright 2012, Royal Society of Chemistry. (b) One-dimensional assembly of triblock (DNA-PEG-DNA) brushes, wherein the middle PEG block serves as a steric block to limit hybridization valency.37 (c) Formation of DNA-backboned bottlebrush superpolymers from DNA-g-PEG grafts via hybridization chain reaction.24


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A second assembly mode regards DNA as a covalent bond-mimic, without requiring a preconstructed DNA template. In order to treat hybridization as bond formation, there must be at least two DNA strands involved (one strand is possible if it contains two separate domains for hybridization). For an analogy in polymer chemistry, a divalent monomer is needed in order to generate a linear polymer. Caruso et al created two complementary PNIPAM-g-DNA grafts containing polyT and polyA sequences.74 The two graft copolymers can “react” and “crosslink” on the surface or colloidal silica microparticles, and via several iterations of layer-by-layer assembly followed by dissolution the colloid template, generate a microcapsule containing DNA and PNIPAM. The presence of the polymer reduces the permeability of the capsules compared with capsules made solely of DNA. This approach is chemically similar to that of gel formation (crosslinking), albeit on the surface of a solid template. Using similar chemistry to form directionally assembled 1-D structures represents a significant challenge, because sphere-like, multivalent agents uniformly interact across their surface, which leads to omnidirectional growth. Zhang et al approached this problem by designing triblock bottlebrush polymers as “macromonomers”, with the first and the third blocks selectively functionalized with DNA (2-5 strands of DNA per block), and the middle block being much longer (>30 repeating units) and functionalized with PEG side chains (Figure 5b).37 The directionality of assembly in this case derives from the PEG side chains, which act as a steric steer. The DNA strands links these macromonomers in one direction to form worm-like “superpolymers” via a step-growth, polycondensation mechanism, with occasional defects (branching). The same group also reported a DNA-backboned bottlebrush structure with PEG side chains, in an attempt to improve the biopharmaceutical properties of oligonucleotide therapeutics (Figure 5c).24 In this study, a PEG


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chain is attached to a nucleobase that is in the middle of hairpin DNA strands. The hairpin is designed to undergo hybridization chain reaction (HCR), which is a form of living polymerization that employs two DNA hairpins as monomers. The polymerization is initiated by the addition of an initiator DNA, which opens up one of the hairpin strands to reveal a singlestranded region that can open up the second hairpin, which reveals another single-stranded region that is identical to the original initiator. The step-growth cascade of strand displacement reactions generated a linear, DNA-backboned bottlebrush assembly with PEG side-chains, with an average length of around 200 nm. The excluded volume effect and steric hindrance of the dense PEG side chains enhanced thermal and nuclease stabilities of the DNA, respectively, and led to improved pharmacokinetics in vivo. Assemblies involving both polymer-polymer interactions and DNA base recognition. Fully hydrophilic DNA-containing copolymers described in the previous section assemble in a similar fashion as free DNA: the polymer component serves only as a passenger. The outcome of assemblies that incorporate both DNA base recognition and polymer-polymer interactions, such as hydrophobic interactions, on the other hand, heavily depends the procedure of the assembly process, i.e. which component assembles first, and the relative strength of the interactions involved.


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Figure 6. Assemblies that involve a two-step (DNA first, polymer second) process. (a) Assembly of PNIPAM-b-dsDNA-b-PNIPAM triblock copolymer to form nanoparticles with surface DNA loops. Reproduced with permission from [75]. Copyright 2013, Royal Society of Chemistry. (b) PNIPAM nanoparticles stabilized with giant DNA tetrahedron ‘surfactants’.76

Ideally, in order to control the assembly process, the conjugate should be fully dispersed in an aqueous solution, and DNA hybridization and polymer interaction can be individually switched on or off. Polymers with an LCST, such as PNIPAM, PPO, and poly(oligo(ethylene glycol) (meth)acrylates), nicely fulfill this role, as their hydrophobic interactions have a built-in thermal on-off switch. Several groups have demonstrated application of this principle using simple, diblock DBCs. For example, Liu77 and Alexander75 et al have shown that two complementary DBCs can hybridize to form a triblock structure, with double-stranded DNA in the middle of two polymer blocks. Increasing the temperature above the polymer LCST results in non-micelle spherical assemblies, presumably with surface-exposed dsDNA (Figure 6a). Had the hydrophobic segment assembled first, the particle surface would likely have a mixture of singlestranded complementary DNA sequences that are unable to fully hybridize, which can cause


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particle-particle aggregation. Along a similar line, O’Reilly et al reported an elegant approach to assemble DNA tetrahedron-PNIPAM conjugates, termed “giant surfactants”, into micelles.76 In this work, a PNIPAM-modified DNA strand, along with three other unmodified DNA strands that are the components of a DNA tetrahedron were co-assembled in one-pot to yield the PNIPAM-modified tetrahedron. While the concentration of the conjugate after DNA assembly is far below the critical micelle concentration (CMC) usually observed for PNIPAM, in the presence of an excess of free PNIPAM, elevation of temperature above the polymer LCST resulted in the formation of micelle-like structures with surface DNA tetrahedra (Figure 6b). Another class of “giant surfactants” were reported by Sleiman et al in a series of studies.78-80 In this case, the hydrophilic segment are DNA nanocages (trigonal prisms, cubes, and pentagonal prisms), but the hydrophobic segments are “precision polymers”, a series of hydrophobic (HE) spacers consecutively appended onto a terminus of a DNA sequence that is complementary to the binding domain of the DNA nanocages. The outcome of the polymer-mediated assembly was found to be “quantized” (1, 2, 3, etc. cages per assembly), and highly sensitive to the degree of polymerization, i.e. the number of the HE units in the hydrophobic block. With increasing polymer length, the assembled structure transitions from individual cages to linear dimers, tetrahedral tetramers, octahedral hexamers, and to higher-order structures (Figure 7a). These supermicelles, with DNA cages containing additional binding domains on their surfaces, were used to generate yet higher order assemblies by introducing linking strands that tether individual cages together, creating a networked aggregate, as manifested by a non-penetrating band in agarose gel electrophoresis.78 The precision polymers used in these constructs are not only precise in length, but also in composition and sequence. In a follow-on study, Sleiman et al introduced hydrophilic, hexaethyloxy gylcol (HEG) units into the HE block.79 The ability to tune


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the strength of the polymer hydrophobic interaction irrespective of the polymer length led to new modes of assemblies, such as donut-shaped cage-ring structures and DNA micelle cages (where the micelle core is within the cage, and the cage itself is the micelle corona). The micelle cage is a particularly interesting structure. By chemically crosslinking the intra-cage micellar core followed by a denaturing process that liberates DNA-polymer nanoparticle out of the DNA nanocage, hexavalent particles with oriented surface DNA strands were obtained (Figure 7b).80 This study is the first example that utilize self-assembly to obtain polymer nanoparticles with monodispersity and prescribed surface DNA patterns, and nicely demonstrates the power of DNA-mediated polymer assemblies.

Figure 7. Different modes of nanocage-mediated copolymer assembly. (a) Quantized assembly of DNA nanocage-based “giant surfactants”, showing increasing aggregation number as a function of hydrophobic block length. Reproduced with permission from [78]. Copyright 2014, Royal Society of Chemistry. (b) The synthesis of hexavalent particles via intrascaffold aggregation and crosslinking, and subsequent removal of the DNA nanocube template. Reproduced with permission from [80]. Copyright 2018, Nature Publishing Group.


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While the DNA micelle cages establish the possibility to use a DNA template to guide polymer assembly on the inside of the scaffold, Liu et al pioneered an approach employing pre-assembled DNA nanostructures to assist hydrophobicity-driven polymer assembly on the outside of the template (termed “frame-guided assembly”).81-85 In this approach, a pre-formed DNA nanostructure (including spherical, cuboid, and prismatic systems) containing a multitude of single-stranded binding domains is functionalized with DNA amphiphiles containing a hydrophobic poly(aryl ether) dendron with eight oligo(ethylene glycol) (OEG) tails. The hydrophobic moieties displayed on the surface of the DNA nanostructures, termed “leading hydrophobic groups (LHGs)”, cannot cause self-aggregation due to the presence of the OEG moieties and the spacing of the LHGs, but can guide additional amphiphilic polymers to fill in the gaps between LHGs, leading to the formation of heterovesicles of prescribed shapes and sizes (Figure 8a). With this templated method, various polymers (poly(benzyl ethers), PPO, etc) have been used to form a variety of shaped structures (cubes, spheres, sheets, etc).


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Figure 8. DNA as a scaffold to guide the assembly of hydrophobic dendrons. (a) Frame-guided assembly though pre-assembled DNA cubic origami. Reproduced with permission from [83]. Copyright 2016, Wiley-VCH. (b) Dendrimer hydrophobicity-driven folding of pre-formed DNA origami sheets.

It is important to recognize the relative strengths of polymer hydrophobic interactions and DNA hybridization, which may be taken advantage of to produce kinetically trapped assemblies or to alter the morphology of an existing assembly. When the hydrophobic interactions of the polymer are strong, for example in the case of PS below its glass transition temperature, it is difficult for DNA-related interactions to alter the morphology of the assembled structure.57 However, in the case of more mobile polymers chains in the hydrophobic domain, shape-shifting of the assembly is possible if DNA hybridization provides a driving force. For example, Herrmann et al reported shape-shifting spherical micelles consisting of DNA-b-PPO. Hybridization with short sequences in the micelle corona does not change the structure of the micelles. However, when long DNA strands that encode several repeating sequences complementary to the corona were employed for hybridization, the spherical assemblies appear to be stripped apart to form linear, double-stranded DNA with pendent PPO. Two of these double helical units then parallelly combine to form highly uniform rod-like aggregates. In another case, Liu et al reported a scenario where polymer hydrophobic interactions outweigh the stiffness of a pre-assembled origami (Figure 8b). In this study, hydrophobic poly(aryl ether) dendrons were displayed on one side of the surface of 100 × 70 nm rectangles with a height of 2 nm. Atomic force microscopy images reveal that some of these rectangles folded upon themselves due to the hydrophobic attraction of the dendrons, to produce taller (6 nm), 100 × 40


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nm and 50 nm × 70 nm rectangular “tacos” (roughly half of the length or width of the expected structure), with two layers of DNA origami and one layer of dendrons in between. Sandwich-like dimers of the rectangles were also observed. Summary. With the availability of DNA-containing copolymers improving significantly, DNA has become an attractive material to mediate the self-assembly of polymers. A synergistic combination of DNA with organic polymers has not only yielded new possibilities in assembly such as long-range ordering, dynamic assemblies, directional display, and polymer sequence control, but also novel physical and bio-activities of the DNA component imparted to the conjugates by the polymer. We anticipate that, with the key language for assembly defined for these materials, novel DNA-containing copolymer self-assemblies with structural and/or functional significance will see an exponential growth and adoption for a variety of applications.

AUTHOR INFORMATION Corresponding Author Runhua Chen: [email protected] Ke Zhang: [email protected] ORCID Ke Zhang: 0000-0002-8142-6702 Notes The authors declare no competing financial interest.


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ACKNOWLEDGMENT KZ acknowledges supported by the National Institutes of Health (the National Institute of General Medical Sciences Award Number 1R01GM121612-01) and the National Science Foundation (CAREER Award Number 1453255). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Science Foundation.

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Self-Assembly of DNA-Containing Copolymers - Bioconjugate

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