Programmable Self-Assembly of Protein-Scaffolded DNA

Subscriber access provided by WESTERN SYDNEY U

Letter

Programmable Self-Assembly of Protein-Scaffolded DNA Nanohydrogels for Tumor-Targeted Imaging and Therapy Na Li, Xiu-Yan Wang, Mei-Hao Xiang, Jin-Wen Liu, Ru-Qin Yu, and Jian-Hui Jiang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b05706 • Publication Date (Web): 31 Jan 2019 Downloaded from http://pubs.acs.org on February 1, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry

Programmable Self-Assembly of Protein-Scaffolded DNA Nanohydrogels for Tumor-Targeted Imaging and Therapy Na Li, Xiu-Yan Wang, Mei-Hao Xiang, Jin-Wen Liu*, Ru-Qin Yu, and Jian-Hui Jiang* State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan 410082, China ABSTRACT: DNA hydrogels are biocompatible and are suitable for many biomedical applications. However, to be useful imaging probes or drug carriers, the ordinary bulk size of DNA hydrogels must be overcome. Here we put forward a new strategy for fabricating a novel and simple protein-scaffolded DNA nanohydrogel, constructed through a direct DNA selfassembly using three types of streptavidin (SA)-based DNA tetrad, for the activation of imaging and targeting therapy of cancer cells. The DNA nanohydrogels are easily prepared and, we show that, by varying the initial concentration of DNA tetrad, it is possible to finely control their size within nanoscale range, which are favorable as carriers for intracellular imaging and transport. By further incorporating therapeutic agents and tumor-targeting MUC1 aptamer, these multifunctionalized SA-scaffolded DNA nanohydrogels (SDH) can specifically target cancer cells and selectively release the preloaded therapeutic agents via a structure switching when in an ATP-rich intracellular environment, leading to the activation of the fluorescence and efficient treatment of cancer cells. With the advantages of facile modular design and assembly, effective cellular uptake, and excellent biocompatibility, the method reported here has the potential for the development of new tunable DNA nanohydrogels with multiple synergistic functionalities for biological and biomedical applications.

DNA hydrogels, a type of emerging and unconstrained DNA structures with highly threedimensional networks, which have attracted considerable attention because of their low toxicity, high biocompatibility, and designable responsiveness.1-3 For the preparation of DNA hydrogels, synthetic polymers such as polyacrylamide,4 poly(N-isopropylacrylamide),5 and 6 polypropylene oxide were typically used as backbones to construct DNA hydrogels. In that case, the DNA was first grafted onto polymers and then cross-linked into a hydrogel by DNA self-assembly.7 These polymer-based DNA hydrogels have various potential applications, particularly in biotechnological, biosensing and biomedical fields.8-10 However, the requirements of organic reagents or complex synthetic procedures in the fabrication processes for DNA-polymer hybrids may limit their practical applications in living organisms. Moreover, the polymer networks often increase the difficulty in surface engineering of these polymer-based DNA hydrogels. In comparison to synthetic polymers, the preparation of pure DNA hydrogels composed of only DNA has also been widely studied, owing to the potential advantages that enable to avoid the introduction of toxic reagents and to develop biocompatible hydrogels for biomedical applications.11-14 Nevertheless, most reported methods for the fabrication of DNA hydrogels were uncontrollable, which tend to grow into bulk size of hydrogels, 15-17 and thus, largely confined their efficiency as an intracellular transport carrier, resulting in the inability to apply in living cells. Recently, an intelligent design is introduced

to control the size of DNA hydrogels by using Y-shaped monomer with only one sticky end as a blocking unit for inhibiting the extension of hydrogels.18 These nanoscale DNA hydrogels (nanohydrogels), though enabling to enter into living cells for targeted gene regulation therapy, still require multistep hybridization reactions and complicated designs using multiple oligonucleotide probes. Therefore, the pursuit of a simple and robust strategy for the preparation of highly biocompatible, easily functionalized, and size-controlled DNA nanohydrogels, which exhibit high performance for intracellular application, particularly, for delivering bioactive molecules to targeted cells, remains a great challenge. Protein, an important biological macromolecule, have many remarkable properties including well-defined chain lengths and amino acid sequences, secondary structures and many different functional groups, as well as favorable biocompatibility.19,20 Moreover, protein can provide a promising scaffold for constructing DNA/RNA nanostructures. We previously demonstrated that a novel and simple protein-scaffolded DNA assembly, that is, streptavidin (SA)-based DNA tetrad enable efficient delivery of nucleic acids and in situ ultrasensitive imaging of miRNA based on crosslinked hybridization chain reaction.21 However, it has not been explored for construction of DNA nanohydrogels. Because SA-based DNA tetrad can be readily synthesized using high-affinity SA-biotin interaction and, further, form the assembly via a crosslinked hybridization reaction, the SA-based DNA tetrad has the potential for developing novel DNA

ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

nanohydrogels. Motivated by the hypothesis, we developed a novel protein-scaffolded DNA nanohydrogels with tunable size and stimuli-responsive property for activatable imaging and therapy in tumor-targeted cells, as illustrated in Scheme 1. a

Y1-SA

aptamer

Cy5-Y2-SA

Dox

BHQ3-Y3-SA

b

Scheme 1. Illustrations of the (a) SDH assembly and modification. (b) Application of functionalized Dox-SDHApt for ATP-triggered imaging and therapy in targeted cancer cells.

The protein-scaffolded DNA nanohydrogels were easily prepared by directly assembling using three types of SA-based DNA tetrad (Y1-SA, Y2-SA, Y3-SA). These tiny DNA tetrad developed here are composed of one SA and only four DNA probes, which provided a relatively loose structure, making it possible to hybridize with each other and form DNA nanohydrogels. In our design, Y1 is ATP aptamer sequence that specifically bind to ATP, and Y2 and Y3 were programmable DNA probes that labeled with a fluorescence donor (Cy5) and acceptor (BHQ3) at the appropriate positions, respectively, which both can partially complement with Y1. Furthermore, the complementary sequences between Y2 and Y3 are designed to contain only eight nucleotides so that they do not hybridize with each other at room temperature. However, the stability of hybridization between Y2 and Y3 is largely enhanced when Y1 simultaneously hybridizes with Y2 and Y3. Consequently, Y1, Y2 and Y3 hybridize with each other to form a stable Y-shaped DNA termed as Y-motif. When using corresponding SA-based DNA tetrad (Y1-SA, Y2-SA and Y3-SA) as building blocks, in this way, they can spontaneously self-assembly into SA scaffoldedDNA nanohydrogels (SDH) through crosslinked hybridization reaction (Scheme 1a and S1). In the resultant SDH, the GC base pairs of crosslinked Y-motif networks can provide a faithful loading site for chemotherapeutic drug doxorubicin (Dox), and the fluorescence of Cy5 could be efficiently quenched by BHQ3 due to the close proximity. In addition, to endow the SDH with suitability for tumor-targeting delivery, it was further modified with the MUC1 aptamer, which recognized the overexpressed MUC1 glycoprotein located on the membrane of many cancer cells.22 After incubation of Dox and MUC1 aptamer functionalized SDH (DoxSDH-Apt) with cells, the nanohydrogels were exclusively

accumulated into targeted cancer cells via receptormediated endocytosis (Scheme 1b). Inside the targeted cells, the SDH were disassembled in response to high ATP level in cancer cells, owing to stronger binding of ATP with its aptamer. As a result, the Cy5 fluorescence was recovered and, the preloaded Dox were effectively released through a structure switching, which can induce cancer cell apoptosis. This multifunctionalized SDH with tumor-targeting and stimuli-responsive property may hold great promise for specific cancer activatable theranostics. Previously, various nanomaterials such as gold nanoparticles (AuNPs),23 metal–organic framework (MOF)24 and nanogel25 have been typically applied to construct ATP-responsive transport platforms for intracellular release of Dox. Although success, these nanomaterials usually required complex preparation processes or exhibited a certain degree of cytotoxicity. Moreover, these methods may involve nonspecific intracellular release of Dox because of the vulnerable environmental susceptibility. Compared with the above ATP-responsive Dox-released nanoplatforms, our proposed Dox-SDH-Apt possesses some remarkable features: first, as protein-scaffolded DNA nanohydrogels, the excellent biocompatibility and water solubility can ensure its ideal application in live cells; second, ATP-responsive apamer probe allows for specific release of Dox. In addition, the small molecule ATP easily enter into SDH and then disassemble the Y-motifs network structures, leading to the effective release of Dox and cancer cells treatment. Three DNA probes based on the sequence of ATP aptamer were rationally designed to form the Y-motifs through base-pairing hybridization (Figure S1), which can serve as a versatile building block for loading and activatable release of Dox in response to ATP (Figure S2). We next constructed an ATP-stimuli responsive nanohydrogel through precise self-assembly formation of Y-motif networks by using SA as scaffold for efficient intracellular transport. Gel electrophoresis comfirmed that the DNA tetrads were formed and then they can further self-assemble into larger molecular weight SDH (Figure S3). Subsequently, dynamic light scattering (DLS) and atomic force microscopy (AFM) were both carried out to investigate the size and morphology of SDH. DLS measurement revealed that the hydrodynamic diameter of Y-motif and DNA-SA were around 3.1 and 10.1 nm, respectively, but the diameter of SDH increased to ~ 103.2 nm after self-assembly of DNA tetrads (Figure S4). AFM images further displayed that the SDH was nanoscale and monodispersed spherical structure, and the diameter was dramatically increased as compared to that of Y-motif or DNA-SA (Figure 1a). It is worth mentioning that, our SDH can be synthesized in a precisely controllable manner by simply changing the initial concentration of DNA tetrads (Figure S5). The higher initial concentration, the larger diameter of SDH was obtained. The size controllability for SDH is of great importance to their fate in bloodstream. Previous reports have revealed that the blood circulation


Page 2 of 6

Page 3 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry time of nanoparticles can be effectively extended when the size of is sub-200 nm.26 Hence, 103.2 nm SDH were used for subsequent experiments. In addition, the zeta potential measurements showed that the SDH had a less negative charge as compared to that of Y-motif (Figure S6). This result may be ascribed to the fact that the formed DNA nanohydrogels have tightly packed network structures, which reduced the expose of the negatively charged DNA. Therefore, this simple one-step strategy may provide a versatile approach for construction of various nanohydrogels through rational design and modification of DNA probes. a)

I

II

200 nm -4.0 nm

III

200 nm 6.0 nm

300 nm

-4.0 nm

6.0 nm

b)

c)

d)

e)

-40.0 nm

50.0 nm

Figure 1. (a) AFM images of Y-motif (I), DNA-SA (II) and SDH (III). (b) Fluorescence recovery of SDH with ATP of varying concentration. (c) Selectivity of SDH for ATP. (d) Fluorescence response of Dox toward SDH with varying DNA concentrations. The concentration of Dox were 2 μM. (e) In vitro release of Dox loaded in SDH.

We then examined the fluorescence responses of developed SDH to varying concentrations of ATP. It was found that the fluorescence intensity of Cy5 dynamic increase with increasing concentration of ATP, and ~7fold fluorescence recovery ratio of Cy5 was obtained at ATP concentration of 10 mM (Figure 1b). These observations disclosed that the small molecule ATP was able to effectively enter into SDH and then to disassemble the Y-motifs network structures. The data obtained via gel electrophoresis further verified that ATP can effectively activate the disassembly of SDH (Figure S7). In addition, selectivity assay was performed to evaluate the specificity of SDH for ATP. We observed that 10 mM other ATP analogues, such as CTP, UTP and GTP, none of them was capable of causing evident ﬂuorescence signals toward the developed SDH (Figure 1c). These results suggested that the Y-motif networks in SDH were only dissociated in the presence of ATP, supporting the potential of this SDH for ATP-responsive system in living cells. As mentioned above, the SDH can serve as an excellent vehicles for loading Dox. After incubation of

Dox with SDH, the gradually decrease of fluorescence for Dox was observed with an increasing concentration of SDH (Figure 1d). Then, we evaluated the release kinetics of Dox-SDH by incubation with different concentration of ATP over time. As shown in Figure 1e, a negligible release of Dox was found in the absence of ATP. After the addition of 0.4 mM ATP, only 6.1% of Dox was released from Dox-SDH in the ﬁrst 4 h and then 12.8% within 24 h. However, when adding 10 mM ATP (simulate intracellular ATP concentration), the release efficiency of Dox was remarkably increased, about 33.5% in the first 4 h and 40.2% within 24 h. These findings of ATP-dependent Dox releasing properties are beneficial to cancer therapy, since it is implied that the intercalated Dox is able to be released quickly in ATP-overexpressed cancer cells, and Dox remains entrapped in Dox-SDH at low-concentration ATP environments such as extracellular domain or normal tissues.23-25 In addition, we found that the SDH exhibited resistance ability against 0.25 u/mL of DNase I even after 4 h incubation (Figure S8), which may be attributed to the too high steric hindrance for nuclease to interact with Y-motif DNA networks.8 This excellent nuclease resistance ability of SDH was favorable for complex sample analysis, particularly, for bioanalytical and biomedical applications. To enhance the specific uptake of SDH for targeted cancer cells, the MUC1 aptamer which targets mucin-1 overexpressed MCF-7 cells, but not HepG2 cells that deficient in mucin-1, was selected as the targeting recognition ligand. After incubation with Cy5labeled SDH-Apt, a bright red fluorescence was observed in MCF-7 cells, but not HepG2 cells (Figure S9), indicating the specificity of SDH-Apt for targeted cancer cells. Moreover, the endocytosis pathway of SDH-Apt was also explored in MCF-7 cells (Figure S10). Confocal imaging showed that the uptake for MCF-7 cells was significantly inhibited after incubating with SDH-Apt containing with NaN3, suggesting an energy dependent endocytic pathway. Hoechst

Dox

Cy5

Merged

a)

b)

c)

Figure 2. Confocal microscopy images of MCF-7 cells pretreated with (a) 5 mM Ca2+, (b) medium, (c) 10 μM oligomycin, following by incubation with Dox-SDH-Apt.

Next, we explored the specific cell-targeting capability of Dox-SDH-Apt. For MCF-7 cells incubated with Dox-SDH-Apt, the fluorescence of Dox and Cy5 were directly visualized by confocal imaging. After incubation



for 4 h, we observed that the fluorescence signals of Dox and Cy5 were both obvious in MCF-7 cells, and the Dox signals were mainly accumulated into the cell nucleus and Cy5 signals were mostly distributed in the cytoplasm (Figure 2b and S11). This result demonstrated that the Dox-SDH-Apt can effectively respond to ATP in MCF-7 cells, which activated the fluorescence of Dox and Cy5. An additional cell imaging experiment was performed to study the size effect of Dox-SDH-Apt on the activation efficiency of Dox and Cy5. The results showed that the larger size of Dox-SDH-Apt (~172 nm) can result in a decreased fluorescence of Dox and Cy5 (Figure S 12). To further investigate the ATP-dependent response from Dox-SDH-Apt, the ATP expression level in MCF-7 cells were regulated with some external stimulus. Before incubation with Dox-SDH-Apt, the MCF-7 cells were pretreated with 5 mM Ca2+, a chemical ATP inducer, or 10 μM oligomycin, which suppresses ATP expression.27,28 The confocal imaging revealed that the fluorescence signals of Dox and Cy5 were both remarkably enhanced upon treatment with Ca2+ compared with untreated MCF-7 cells, while relative weaker fluorescence signals were obtained when the cells preincubated with oligomycin (Figure 2). The data indicated that the designed Dox-SDH-Apt held the potential for dynamically sensing the change of ATP expression level and releasing the Dox in a controllable manner, facilitating the development of ATP stimuliresponsive nanoplatform for activatable imaging and cancer therapy. a)

c) 106

b)

0.1%

0.7%

104 102

d) 106

0.1%

0.5%

104

94.7%

103

4.5%

105

102

107

e) 106

0.7%

22.4%

92.9%

103

6.5%

105

102

107

larger size of Dox-SDH-Apt (~172 nm) to treat MCF-7 cells, the efficiency of killing cancer cells is obvious reduced (Figure S 13), which can be ascribed to the lower Dox releasing. Subsequently, flow cytometric analysis was also performed to demonstrate the apoptosis-inducing capabilities by using AnnexinV-FITC/PI apoptosis detection kit. It was found that, the total apoptotic percentage of early and late apoptotic was only 7.0% in the SDH-Apt treated group (Figure 3d), which was comparable with the control group (5.2%, Figure 3c). Nevertheless, the total apoptotic ratio dramatically increased to 47.9% after treating with Dox-SDH-Apt (Figure 3e), which was much higher than the control group. These observations demonstrated that the developed Dox-SDH-Apt can effectively deliver the chemotherapeutic drug Dox to enhance cancer treatment. In summary, we have used an innovative yet a simple design approach to develop a new DNA nanohydrogel for activable imaging and therapy in targeted cancer cells. The SDH were facilely prepared by direct DNA selfassembly using three types of SA-based DNA tetrad, resulting in many advantages such as high biocompatibility, size controllability and ease of functional modification. The results showed that SDH functionalized with the MUC1 aptamer and Dox (DoxSDH-Apt) can selectively target cancer cells and can be used for ATP-responsive activable imaging and effective therapy for cancer cells. We easily envision that, by relational programmable DNA designs or incorporated other materials, such as nanoparticles, therapeutic proteins/genes and even functionalized nanoparticles, it is possible to allow the development of intelligent DNA nanohydrogels that were generally applicable to various fields, such as tissue engineering, biosensing, cancer therapy, and nanomechanical devices.

ASSOCIATED CONTENT Supporting Information

104

51.4%

103

25.5%

105

107

Figure 3. (a-b) In vitro cytotoxicity of Dox-SDH-Apt on (a) MCF-7 cells, (b) HepG2 cells. (c-e) MCF-7 cells apoptosis induced by (c) PBS, (d) SDH-Apt, (e) Dox-SDH-Apt.

We further investigated the in vitro cytotoxicity of Dox-SDH-Apt against MCF-7 cells and HepG2 cells by using MTS assay. As displayed in Figures 3, SDH-Apt showed negligible toxicity to MCF-7 cells or HepG2 cells within the tested concentrations range, owing to the excellent biocompatibility of our nanocarriers. However, the cell viability of MCF-7 cells was remarkably decreased to below 20% after treating with Dox-SDH-Apt containing 2 μM Dox, while no significant loss of viability to HepG2 cells (Figure 3a and 3b). The finding of dosedependent cytotoxicity for MCF-7 cells implied that the Dox-SDH-Apt had excellent selectivity to targeted MCF-7 cells for ATP-responsive drug release. In addition, comparative experiment revealed that, when using the

Page 4 of 6

The Supporting Information is available free of charge on the ACS Publications website. Experimental section, DNA sequence, Y-motif formation, SDH assembly and disassembly, DLS, DNase I assay, endocytosis research, confocal fluorescence images

AUTHOR INFORMATION Corresponding Author *Fax: +86-731-88821916. *Email: [email protected]; Email: [email protected].

ORCID Jin-Wen Liu: 0000-0001-9340-8109 Jian-Hui Jiang: 0000-0003-1594-4023

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This study was financially supported by the National Natural


Page 5 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Analytical Chemistry Science Foundation of China (21527810, 21705041) and National Key Basic Research Program (2011CB911000).

REFERENCES (1)

(2) (3)

(4) (5)

(6)

(7) (8)

(9)

(10)

(11)

(12)

(13) (14)

Lee, J. B.; Peng, S.; Yang, D.; Roh, Y. H.; Funabashi, H.; Park, N.; Rice, E. J.; Chen, L.; Long, R.; Wu, M.; Luo, D. A mechanical metamaterial made from a DNA hydrogel. Nature. Nanotech. 2012, 7, 816-820. Li, J.; Mooney, D. J. Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 2016, 1, 16071. Li, J.; Mo, L.; Lu, C. H.; Fu, T.; Yang, H. H.; Tan, W. Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications. Chem. Soc. Rev. 2016, 45, 1410-1431. Yang, H.; Liu, H.; Kang, H.; Tan, W. Engineering targetresponsive hydrogels based on aptamer-target interactions. J. Am. Chem. Soc. 2008, 130, 6320-6321. Guo, W.; Lu, C. H.; Qi, X. J.; Orbach, R.; Fadeev, M.; Yang, H. H.; Willner, I. Switchable bifunctional stimulitriggered poly-N-isopropylacrylamide/DNA hydrogels. Angew. Chem., Int. Ed. 2014, 53, 10134-10138. Wu, F.; Zhao, Z.; Chen, C.; Cao, T.; Li, C.; Shao, Y.; Zhang, Y.; Qiu, D.; Shi, Q.; Fan, Q. H.; Liu, D. Selfcollapsing of single molecular poly-propylene oxide (PPO) in a 3D DNA network. Small 2018, 14, 1703426. Wei, B.; Cheng, I.; Luo, K. Q.; Mi, Y. Capture and release of protein by a reversible DNA-induced sol-gel transition system. Angew. Chem., Int. Ed. 2008, 47, 331-333. Dave, N.; Chan, M. Y.; Huang, P. J. J.; Smith, B. D.; Liu, J. Regenerable DNA-functionalized hydrogels for ultrasensitive, instrument-free mercury (II) detection and removal in water. J. Am. Chem. Soc. 2010, 132, 1266812673. Peng, L.; You, M.; Yuan, Q.; Wu, C.; Han, D.; Chen, Y.; Zhong, Z.; Xue, J.; Tan, W. Macroscopic volume change of dynamic hydrogels induced by reversible DNA hybridization. J. Am. Chem. Soc. 2012, 134, 12302-12307. Yan, L.; Zhu, Z.; Zou, Y.; Huang, Y.; Liu, D.; Jia, S.; Xu, D.; Wu, M.; Zhou, Y.; Zhou, S.; Yang, C. J. Targetresponsive “sweet” hydrogel with glucometer readout for portable and quantitative detection of non-glucose targets. J. Am. Chem. Soc. 2013, 135, 3748-3751. Cheng, E.; Xing, Y.; Chen, P.; Yang, Y.; Sun, Y.; Zhou, D.; Xu, L.; Fan, Q.; Liu, D. A pH-triggered, fast-responding DNA hydrogel. Angew. Chem., Int. Ed. 2009, 48, 76607663. Xing, Y.; Cheng, E.; Yang, Y.; Chen, P.; Zhang, T.; Sun, Y.; Yang, Z.; Liu, D. Self-assembled DNA hydrogels with designable thermal and enzymatic responsiveness. Adv. Mater. 2011, 23, 1117-1121. Zhang, L.; Jean, S. R.; Ahmed, S.; Aldridge, P. M.; Li, X.; Fan, F.; Sargent, E. H.; Kelley, S. O. Multifunctional quantum dot DNA hydrogels. Nat. Commun. 2017, 8, 381. Zhang, L.; Lei, J.; Liu, L.; Li, C.; Ju, H. Self-assembled DNA hydrogel as switchable material for aptamer based fluorescent detection of protein. Anal. Chem. 2013, 85, 11077-11082.

(15) Um, S. H.; Lee, J. B.; Park, N.; Kwon, S. Y.; Umbach, C. C.; Luo, D. Enzyme-catalysed assembly of DNA hydrogel. Nat. Mater. 2006, 5, 797-801. (16) Park, N.; Um, S. H.; Funabashi, H.; Xu, J.; Luo, D. A cellfree protein-producing gel. Nat. Mater. 2009, 8, 432-437. (17) Nishikawa, M.; Mizuno, Y.; Mohri, K.; Matsuoka, N.; Rattanakiat, S.; Takahashi, Y.; Funabashi, H.; Luo, D.; Takakura, Y. Biodegradable CpG DNA hydrogels for sustained delivery of doxorubicin and immunostimulatory signals in tumor-bearing mice. Biomaterials 2011, 32, 488494. (18) Li, J.; Zheng, C.; Cansiz, S.; Wu, C.; Xu, J.; Cui, C.; Liu, Y.; Hou, W.; Wang, Y.; Zhang, L.; Teng, I. T.; Yang, H. H.; Tan, W. Self-assembly of DNA nanohydrogels with controllable size and stimuli-responsive property for targeted gene regulation therapy. J. Am. Chem. Soc. 2015, 137, 1412-1415. (19) Wu, Y.; Chakrabortty, S.; Gropeanu, R. A.; Wilhelmi, J.; Xu, Y.; Er, K. S.; Kuan, S. L.; Koynov, K.; Chan, Y.; Weil, T. pH-responsive quantum dots via an albumin polymer surface coating. J. Am. Chem. Soc. 2010, 132, 5012-5014. (20) Wu, Y.; Pramanik, G.; Eisele, K.; Weil, T. Convenient approach to polypeptide copolymers derived from native proteins. Biomacromolecules 2012, 13, 1890-1898. (21) Huang, D. J.; Huang, Z. M.; Xiao, H. Y.; Wu, Z. K.; Tang, L. J.; Jiang, J. H. Protein scaffolded DNA tetrads enable efficient delivery and ultrasensitive imaging of miRNA through crosslinking hybridization chain reaction. Chem. Sci. 2018, 9, 4892-4897. (22) Fan, Z.; Sun, L.; Huang, Y.; Wang, Y.; Zhang, M. Bioinspired fluorescent dipeptide nanoparticles for targeted cancer cell imaging and real-time monitoring of drug release. Nature Nanotech. 2016, 11, 388-396. (23) Li, N.; Xiang, M. H.; Liu, J. W.; Tang, H.; Jiang, J. H. DNA polymer nanoparticles programmed via supersandwich hybridization for imaging and therapy of cancer cells. Anal. Chem. 2018, 90, 12951-12958. (24) Chen, W. H.; Yu, X.; Liao, W. C.; Sohn, Y. S.; Cecconello, A.; Kozell, A.; Nechushtai, R.; Willner, I. ATP-responsive aptamer-based metal-organic framework nanoparticles (NMOFs) for the controlled release of loads and drugs. Adv. Funct. Mater. 2017, 27, 1702102. (25) Mo, R.; Jiang, T.; DiSanto, R.; Tai, W.; Gu, Z. ATPtriggered anticancer drug delivery. Nat. Commun. 2014, 5, 3364. (26) Pouton, C. W.; Seymour, L. W. Key issues in non-viral gene delivery. Adv. Drug Delivery Rev. 2001, 46, 187-203. (27) Qiang, W.; Hu, H.; Sun, L.; Li, H.; Xu, D. Aptamer/polydopamine nanospheres nanocomplex for in situ molecular sensing in living cells. Anal. Chem. 2015, 87, 12190-12196. (28) Wu, C.; Chen, T.; Han, D.; You, M.; Peng, L.; Cansiz, S.; Zhu, G.; Li, C.; Xiong, X.; Jimenez, E.; Yang, C. J.; Tan, W. Engineering of switchable aptamer micelle flares for molecular imaging in living cells. ACS Nano 2013, 7, 57245731.



Page 6 of 6

Table of Contents (for TOC only)


6

Programmable Self-Assembly of Protein-Scaffolded DNA

Recommend Documents