Article pubs.acs.org/Langmuir
X‑DNA Origami-Networked Core-Supported Lipid Stratum Seung Won Shin,† Kyung Soo Park,† Min Su Jang,† Woo Chul Song,† Jin Kim,§ Seung-Woo Cho,§ Joo Young Lee,∥ Jeong Ho Cho,†,‡ Sunghwan Jung,⊥ and Soong Ho Um*,†,‡ †
School of Chemical Engineering and ‡SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon 440-746, South Korea § Department of Biotechnology, Yonsei University, Seoul 120-749, South Korea ∥ College of Pharmacy, The Catholic University of Korea, Buchoen 420-743, South Korea ⊥ Department of Engineering Science and Mechanics, Virginia Tech, Blacksburg, Virginia 24061, United States S Supporting Information *
ABSTRACT: DNA hydrogels are promising materials for various fields of research, such as in vitro protein production, drug carrier systems, and cell transplantation. For effective application and further utilization of DNA hydrogels, highly effective methods of nano- and microscale DNA hydrogel fabrication are needed. In this respect, the fundamental advantages of a core−shell structure can provide a simple remedy. An isolated reaction chamber and massive production platform can be provided by a core−shell structure, and lipids are one of the best shell precursor candidates because of their intrinsic biocompatibility and potential for easy modification. Here, we demonstrate a novel core−shell nanostructure made of gene-knitted X-shaped DNA (X-DNA) origami-networked gel core-supported lipid strata. It was simply organized by cross-linking DNA molecules via T4 enzymatic ligation and enclosing them in lipid strata. As a condensed core structure, the DNA gel shows Brownian behavior in a confined area. It has been speculated that they could, in the future, be utilized for in vitro protein synthesis, gene-integration transporters, and even new molecular bottom-up biological machineries.
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INTRODUCTION Several man-made multicompartmental nanoarchitectures have been produced. Core−shell structures, for example, have become popular because of their unique physicochemical features such as improved photophysical properties, electroconductivity, surface adjustability, controllable biocompatibility, and thermal or pH responsiveness, as compared to their singular-component counterparts.1−4 According to the controllable variation in either core or shell precursors, the outcomes have been distinctly and appropriately exploited for use in drug transport, molecular imaging, immunodiagnostics, and even tumor therapeutics.5−11 As a shell precursor, liposomes have several intrinsic advantages including biodegradability, nontoxicity, nonimmunogenicity, and the capacity for easy modification.12−16 Additionally, liposomes have received much attention as reaction chambers for separate but simultaneous reactions.15−19 Macromolecules such as proteins and nucleotides can be effectively encapsulated in liposomes and isolated from each other.15,16 Thus, many single-molecule reactions can be achieved by utilizing liposomes and are carried out for delivery.15,16 DNA hydrogels can be synthesized by cross-linking blocks of DNA such as X-shaped DNA (X-DNA) via enzymatic ligation. It is an attractive material because of its biocompatibility and unique physiochemical properties, including its adjustable porosity and electrochemical capacity.20 Possible applications range from in vitro protein production to drug carrier systems to cell transplantation and even energy storage.21−26 However, © 2015 American Chemical Society
the use of specific mold systems to control the DNA hydrogel size is essential.27,28 Therefore, size and yield limitations exist in DNA hydrogel fabrication. Here, we present a novel system for nano- or microscale DNA hydrogel fabrication using a liposomes as a reaction sac. Nano- or micro-core−shell structures consisting of X-DNA origami-networked core−shell and lipid−shell structures were obtained.
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EXPERIMENTAL SECTION
Preparation of X-DNA. Detailed descriptions of the X-DNA block have been published.21,23 Single-stranded DNA sequences (e.g., X1, X2, X3, and X4) used in the experiment were noted in Figure S1. The X-DNA origami was synthesized by simply mixing the four single oligonucleotides (designated as Xn, with n = 1, 2, 3, 4) shown in Figure S1 with simultaneous processing under sequential thermal fluctuation as presented by the previous study.21,23 Fabrication of X-DNA Origami-Networked Core-Supported Lipid Strata. Briefly, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) (2 mg), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′rac-glycerol) (POPG) (0.2 mg), Texas Red-conjugated 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (Texas Red DHPE) (25 μg), and cholesterol (0.4 mg) were mixed thoroughly and dried to create the lipid layer. Ethyl acetate was then poured into a dried lipid layer to a lipid concentration of 5.2 mg/mL. To dissolve all lipids completely, the mixture solution was held at 50 °C for 20 min. For an Received: September 19, 2014 Revised: December 28, 2014 Published: January 13, 2015 912
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Figure 1. Schematic drawing of an X-DNA origami core-supported lipid strata structure consisting of an outer lipid strata and a central X-DNA gel core and an evaluation of the external morphologies. (a) Sketch of the DNA gel core-supported lipid strata showing that the outer shell and inner core are composed of lipid strata (red) and a T4 (blue) enzymatically ligated X-DNA origami (gray/green) networked core, respectively. (b, c) External morphologies shown using a CLSM and TEM. To maximize the resolution of the CLSM, larger DNA gel core-supported lipid strata, approximately 5 to 10 μm in size, were manufactured. In the TEM image, we observed that the DNA gel core in black was fabricated in the relatively bright nanoscaled lipid strata.
Figure 2. X-DNA origami-networked core formation in lipid strata. (a) X-DNA was encircled by lipid boundaries and remained inside, even in the absence of T4 ligase (left upper). X-DNA origami cross-links inside the lipid strata and forms the X-DNA gel core (left below). Gel electrophoretic images of the DNA hydrogel core as compared to free X-DNA in the controls; the higher locations of T4 ligase-containing samples (lane 3 on the right) indicate the formation of the DNA hydrogel. (b) Before incubation for cross-linking, X-DNA were evenly dispersed in the lipid strata (upper). After incubation, DNA hydrogel cores were formed (below). inner solution, X-DNA (3.5 nmoles) was mixed thoroughly with 15 units of T4 DNA ligase, 10× ligase buffer, SYBR Green I (1000×, 5 μL), inner buffer solution (175 mM glucose, 75 mM sucrose) (5 μL), and nuclease-free water (up to 50 μL). The 10× ligase buffer is consisted of Tris-HCl (300 mM, pH 7.8), MgCl2 (100 mM), dithiothreitol (100 mM), and ATP (10 mM). Prepared mixtures were added to phospholipid solutions dissolved in ethyl acetate. The mixtures were emulsified for 10 s to form water-in-oil emulsions with a tip sonicator to fabricate nanoscaled emulsions. In the case of microscaled emulsion fabrication, mixtures were vigorously stirred with a magnetic stir bar for 15 min. Immediately after emulsification, the emulsion solutions were gently placed in 400 μL of an additional aqueous outer solution and successively centrifuged at 16 100g and 4 °C for 30 min. The outer solution was composed of a 250 mM glucose solution (40 μL), T4 DNA ligase 10× buffer (40 μL), and nucleasefree water (320 μL). Although water-in-oil emulsions were produced via an interphase between ethyl acetate and the outer solution, emulsions of inner solutions were encapsulated in unilamellar vesicles
consisting of lipid strata. Because the density of the inner solutions was higher than that of the outer solutions, inner solutions encapsulated in lipid strata were pelleted on the bottom of the tube. Pellets were recollected using a syringe in order to avoid direct contact with organic phases. The collected pellets were cured at room temperature for 3 h to produce a cross-linked network gel matrix among X-DNAs. Detail descriptions of the used materials are noted in the Supporting Information.
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RESULTS AND DISCUSSION Construction of a Lipid-Enveloped X-DNA Origami Core−Shell Structure. In Figure 1a, the structure is divided into two parts, with X-DNA origami networks as an inner solution and lipid components as an outer solution. To induce self-ligation among X-DNAs, each oligonucleotide of X-DNA had a palindromic overhang sequence (ACGT). Additional details regarding the sequence and preparative method for X913
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performed. Both samples and controls are denoted in the double-positive region in the flow cytometry data (Figure 3a,b).
DNA are provided in Figure S1. The resulting fabricated lipid strata contained an average of 82% of the initial X-DNA (Figure S2). We show that the lipid strata structure remained constant during incubation (Figure S3). It can be assumed that each shell acts individually as a single reactor for each X-DNA gel formation. To confirm each component, the lipid strata and DNA gel core were selectively stained with Texas Red DHPE and SYBR Green I, respectively. Figure 1b,c demonstrates the condensed volumes of the DNA gel core. The mean diameter of the DNA gel cores can vary in the range of micro- to nanometers depending on the size of the outer lipid strata mold, and this was observed even when a bulky DNA gel was formed. Generally, the bulky DNA gel occupied almost 70% of the total reaction volume28 and may be induced by a sol-gel phase transition.29,30 In Figure 1b, microsized samples were prepared for CLSM imaging. The smaller green spheres represent the DNA gel core and are outlined in red corresponding to the lipid strata. This core− shell structure also can be obtained on the nanoscale, which can be confirmed by TEM analysis (Figure 1c). During TEM analysis, both the DNA gel core and lipid strata were stained with uranyl acetate. A darker region at the core indicates the existence of the condensed DNA gel. Also, the lowermagnification TEM image indicates that the fabrication efficiency of the core X-DNA gel is relatively higher. (Figure S4). Evidence of an X-DNA Origami Gel Core in Lipid Envelops. We tested various parameters during core synthesis and determined that the gel core was made entirely of ligated X-DNA origami networks formed in the lipid strata. All components were the same with the exception of nuclease-free water used as a negative control instead of T4 ligase. As shown in the upper left part of Figure 2a, the T4 ligase-free negative control group has an evenly distributed green color. This indicates that the X-DNA did not condense. The sample containing T4 ligase solutions exhibited a condensed DNA gel core surrounded by external lipid strata (note the bottom right of Figure 2a). Evidence of T4 ligase activity upon X-DNA gel core formation is also supported by a gel electrophoretic migration assay. The size of the X-DNA increases with the process of ligation; thus, by observing the retardation of the bands during electrophoresis, it is possible to determine whether ligation has occurred. Prior to gel electrophoresis, the lipid strata were first removed with a 5% Triton X-100 solution. The T4 ligase-free control exhibits a strong single band of nonligated, free X-DNAs, as shown on the right of Figure 2a; however, X-DNA origami-networked cores are displayed at a relatively higher position, which may be ascribed to the larger molecular weight causing slow retardation (note lane 3 on the right in Figure 2a). Furthermore, the formation of an X-DNA gel core was tracked according to the time interval. As shown on the left in Figure 2b, no shrunken DNA crosslinks appeared at the initial time. During gelation, however, the X-DNA gel core formed in the lipid strata (Figure 2b, below). Therefore, it is clear that the X-DNA gel core was formed via T4 enzymatic activation inside the structure. The presence of X-DNA gel cores in the confined area was further confirmed using flow cytometric analysis. X-DNA origami with blunt ends (designated as blunt X-DNA) was selected as a control in order to block the T4 ligation efficiency among X-DNAs (Figure S5). After both lipid strata and X-DNA were stained with Texas Red DPHE and SYBR Green I dyes, respectively, successive flow cytometric measurements were
Figure 3. Evidence of the formation of X-DNA origami-networked, core-supported, lipid core−shell structures was evaluated using flow cytometry. (a) When the outer lipid strata encapsulated stained XDNA, 96.7% of the liposomes were located in the double-positive region. (b) Blunt X-DNA was used to prepare the control group, and (c) and (d) show the locations of lipid strata with X-DNA removed and blunt X-DNA, respectively. With ligated X-DNA, which forms the X-DNA gel core, 31.7% of samples were located in a single-positive region, whereas only 18.5% of blunt X-DNA was located in a singlepositive region.
After selective removal of lipid strata with Triton X-100, the bare X-DNA core gel represented 35.4% of the total composition in the SYBR Green I single-positive region (Figure 3c). Meanwhile, a relatively smaller proportion of blunt X-DNA from the control group was denoted in the SYBR Green I single-positive region (∼18.5%), as shown in Figure 3d. With respect to the relative SYBR Green I emission, X-DNA gel networks exhibited a higher intensity than blunt X-DNAs. Additionally, the thermal properties of the X-DNA gel coresupported lipid strata were evaluated. The melting temperature (Tm) of the lipid strata was measured with or without the XDNA inside the structure (Figure S6). Previously, interaction between DNA and lipid has been shown to increase the Tm value of liposome.31 As expected, the Tm was increased from 3 to 4 °C when free X-DNA molecules were encapsulated in lipid strata; during X-DNA gel core formation, the lipid strata Tm was decreased to 3.4 °C. We assume that the effect of X-DNA on the lipid strata was decreased because of the formation of an X-DNA gel core. Physiochemical Properties of the Lipid StrataSupported X-DNA Origami Gel. The size of the complete lipid strata-supported X-DNA gel core differs from that of a single X-DNA gel core, which was recovered by stripping off the lipid strata (Figure 4). The difference in mean diameter of nanosized X-DNA gel core-supported lipid strata was measured using DLS. In Figure 4a, the red and green lines represent the size variations in complete X-DNA gel core-supported lipid strata and the X-DNA gel core alone, respectively. The mean diameter of the exterior lipid strata was 449.3 ± 100.3 nm, and that of the X-DNA core was 264.4 ± 28.0 nm. Inside the lipid strata, the X-DNA gel core occupied approximately 20.4 vol % 914
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Figure 4. Diameter of the DNA gel core alone or X-DNA gel coresupported lipid strata measured with DLS. (a) The size of the nanosized X-DNA origami-networked core-containing lipid strata corresponds to the red line, and the lipid-removed X-DNA gel core is indicated by a green line. (b) DNA gel condensation in the lipid shell was measured under confocal laser scanning microscopy and TEM. The upper two images show that the X-DNA origami-networked core is smaller in diameter than the outer lipid strata (at a diameter ratio of 3.08 to 5.56 μm for the X-DNA origami-networked core and lipid strata). Most of the X-DNA gel core-supported lipid strata were statistically similar. The two bottom views were obtained via TEM and indicate that uranyl acetate staining causes the X-DNA gel core in the nanoscale lipid strata to appear shrunken.
Figure 5. In-situ monitoring of the Brownian motion of a single XDNA gel core in lipid strata. (a) Random motion in the X-DNA gel core observed via tracking analysis of serial confocal laser scanning microscopic images at specific time intervals. The capture time of each image was noted during imaging. SYBR Green I-stained X-DNA gel cores, shown in green, emerged in different areas of the lipid layers, shown in red. (b) The relative location of the X-DNA gel core was coordinated against the center of the outer lipid strata. (c) The X−Y coordinates of the moving X-DNA gel core in each captured image were plotted in the plane, and moving directions were tracked using black lines connecting the green dots.
experimental MSD was 4.796 × 10−13 m2. When the simulated MSD value was in the range of 4.107 × 10−13−5.117 × 10−13 m2, the observed MSD was in the simulated range. Accordingly, it is implied that the random movements of the X-DNA gel core in the lipid strata must be caused by Brownian motion.
on average. External images are shown in Figure 4b. In both cases of microsized and nanosized X-DNA origami-networked core-supported lipid strata, shrinkage of the X-DNA gel core was confirmed. The measured diameters of lipid strata and the X-DNA gel core were noted in the images with red and green letters, respectively. Because the samples were dried for TEM analysis, the size of the particulates was smaller than the hydrodynamic size as measured by DLS because of shrinkage. Because of the larger volumes of the lipid shells, we observed the Brownian motion of a single X-DNA gel core in the inner part of the complete structure. Serial CLSM imaging was used to confirm the moving patterns of the X-DNA core in the lipid strata. The Brownian behavior of the X-DNA gel core was theoretically calculated and further validated with experimental data. We monitored the locations of single X-DNA gel cores (Figure 5a) for specific time intervals. The entire area of the lipid strata was plotted, and each location at a given time was coordinated along the center (Figure 5b). Each coordinate and moving direction of the X-DNA gel core inside the lipid strata were marked on the plane core. The serial images of the XDNA gel core are shown in Figure 5c. To ensure that the motion was Brownian, we used the MATLAB program to simulate the behavior of the X-DNA gel marked by the coordinates, followed by calculations of both the square and mean square displacement (MSD) (Figure S7, Figure S8). The
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CONCLUSIONS AND OUTLOOK We have created a new core−shell nanostructure involving both the X-DNA gel core and lipid strata. This study demonstrates the presence of X-DNA condensation in both the nano- and microscale core−shell, thus exposing volumetric aqueous boundaries between the lipid strata and X-DNA gel core. The isolated X-DNA gel cores within aqueous boundaries displayed Brownian motion. We anticipate that this novel core−shell structure will provide a multipotent synthetic architecture for use in a variety of research fields as a bio- or chemosensor and reactor, particularly in physiological research.
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ASSOCIATED CONTENT
S Supporting Information *
Materials and experimental procedures, theoretical analysis of the Brownian motion of the X-DNA core within lipid strata, MATLAB information, and physicochemical characterization of the X-DNA origami-networked core-supported lipid stratum. This material is available free of charge via the Internet at http://pubs.acs.org. 915
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI14C3301) and by Basic Science Research Programs through the National Research Foundation (NRF) funded by the Ministry of Science ICT and Future Planning (grant nos. 2013R1A1A1058670 and 2013R1A1A2016781).
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