DNA-Encoded Raman-Active Anisotropic Nanoparticles for microRNA

Aug 29, 2017 - The development of highly sensitive and selective methods for the detection of microRNA (miRNA) has attracted tremendous attention beca...
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DNA-Encoded Raman-Active Anisotropic Nanoparticles for microRNA Detection Lin Qi,† Mingshu Xiao,† Xiwei Wang,† Cheng Wang,‡ Lihua Wang,§ Shiping Song,§ Xiangmeng Qu,† Li Li,† Jiye Shi,∥ and Hao Pei*,† †

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, P. R. China ‡ Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, P. R. China § Division of Physical Biology & Bioimaging Center, Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, P. R. China ∥ Kellogg College, University of Oxford, Oxford OX2 6PN, U.K. S Supporting Information *

ABSTRACT: The development of highly sensitive and selective methods for the detection of microRNA (miRNA) has attracted tremendous attention because of its importance in fundamental biological studies and diagnostic applications. In this work, we develop DNA-encoded Raman-active anisotropic nanoparticles modified origami paper analytical devices (oPADs) for rapid, highly sensitive, and specific miRNA detection. The Raman-active anisotropic nanoparticles were prepared using 10-mer oligo-A, -T, -C, and -G to mediate the growth of Ag cubic seeds into Ag nanoparticles (AgNPs) with different morphologies. The resulting AgNPs were further encoded with DNA probes to serve as effective surface-enhanced Raman scattering (SERS) probes. The analytical device was then fabricated on a single piece of SERS probes loaded paper-based substrate and assembled based on the principles of origami. The addition of the target analyte amplifies the Raman signals on DNA-encoded AgNPs through a target-dependent, sequence specific DNA hybridization assembly. This simple and low-cost analytical device is generic and applicable to a variety of miRNAs, allowing detection sensitivity down to 1 pM and assay time within 15 min, and therefore holds promising applications in point-of-care diagnostics. molecular cloning,22 fluorescent technology,23,24 isothermal amplification methods,25,26 real-time quantitative polymerase chain reaction,27 hybridization-based microarray,28 electrochemical methods,5,12,29 and nanoparticle amplification methods. 30,31 Nevertheless, these methods still have some limitations. Many current techniques often require expensive and cumbersome instruments, specialized skills, or involve multiple steps and are time-consuming. On the other hand, some techniques lack of specificity and selectivity due to the disability to distinguish highly related miRNAs. Thus, their practical use for miRNA detection in theranostic applications is still hindered. Therefore, it is in great demand to develop a rapid, simple, highly sensitive, and selective miRNA detection platform for applications in complex biological environments. Since its discovery in 1974, surface-enhanced Raman spectroscopy (SERS) has soon emerged as a powerful tool for biological analysis owing to its high sensitivity, noninvasive, and

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ince initially identified in Caenorhabditis elegans in 1993,1 microRNAs (miRNAs), as a type of endogenous, noncoding single-stranded RNA molecules with 19−23 nucleotides, have attracted tremendous attention because of their pivotal regulatory roles in plants and animals.2,3 In the past few decades, miRNAs have been reported to play important roles in regulating many important biological processes, including cell growth, cell differentiation, apoptosis, and transcription level of gene expression.4−7 Moreover, it is well-acknowledged that specific changes in miRNAs expression patterns are directly correlated with various diseases,8−12 and miRNAs also can serve as important biomarkers for cancer diagnostics and screening.13−17 Given their importance in fundamental biological studies and diagnostic applications, it is thus highly desirable to develop a sensitive and specific analytical method for the miRNAs assay. However, the miRNA detection is still hindered by its short length, sequence similarity among family members, low cellular abundance, and susceptibility to degradation.18−20 In the past decades, many techniques have been developed for the detection of miRNA, including Northern blotting,21 © XXXX American Chemical Society

Received: May 17, 2017 Accepted: August 16, 2017

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DOI: 10.1021/acs.analchem.7b01861 Anal. Chem. XXXX, XXX, XXX−XXX

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Analytical Chemistry nondestructive fingerprint characterization, and simple and fast preparation.32−40 Colloidal aggregates have been the most widely used SERS substrates, with good sensitivity down to single-molecule level. However, colloidal aggregates lack the selectivity that is of critical importance for real world applications. Paper has recently emerged as the material of choice for the fabrication of point-of-care diagnostic and analytical devices since it is simple, low-cost, disposable, and eco-friendly.41,42 In this study, to address the aforementioned challenges, we developed DNA-encoded Raman-active anisotropic nanoparticles modified origami paper analytical devices (oPADs) for rapid, sensitive, and specific miRNA detection. Considering the strong plasmonic property, in this design, we employed Ag nanoparticles (AgNPs) and DNA encoding to control their assembly to selectively turn on the SERS enhancement in a target-dependent, sequence-specific manner. The DNA-encoded SERS probes were loaded onto a single piece of flat paper that has been wax-patterned with channels and then assembled into a low-cost and simple paper-based analytical device using the principles of origami. We further demonstrated that the DNA-encoded Raman-active anisotropic nanoparticles modified oPADs can serve as a rapid and highly sensitive multiplex miRNA assay.

particle size and shape of Ag seeds were determined by electron microscopy. Synthesis of the DNA-Encoded Raman-Active Anisotropic Nanoparticles. The concentration of the purified 40 nm silver nanocubes was measured by inductively coupled plasma mass spectrometry (ICP-MS) with results of about 8.8 × 109 particles/mL. According to previous study, the procedure to synthesize DNA-encoded Raman-active anisotropic nanoparticles was performed as followed:44 10 μL of 500 μM C10 (or A10, T10, G10) was added into 100 μL above cubic Ag seeds solution and incubated for 20 min to allow the DNA to adsorb onto the silver seeds. In order to affect the nanoparticle morphology during growth, excess amounts of DNA were used here. Next, 1.5 μL of 70 mM AA and 10.1 μL of 2 mM AgOAc were introduced to initiate the reduction reaction. The reaction was proceeded for 3 h until no further color change was observed. DNA-encoded Raman-active anisotropic nanoparticles were thus obtained. DNA functionalization on AgNP surfaces showed high stability and biorecognition capabilities.44 Preparation of SERS Probes. To prepare SERS probes, the as-synthesized Ag−C10 (600 μL, 0.11 nM) was modified with probe A (100 μM, 4 μL) and probe B (100 μM, 4 μL), followed by the addition of sodium citrate (500 mM, pH 3.0, 12 μL). The solution was then incubated for 30 min at ambient temperature, followed by centrifugation at 10000 rpm for 15 min at 4 °C. The supernatant containing unmodified DNA was removed and the precipitate was redispersed with 10 mM PB solution (pH 7.4). The procedure was repeated for three times. Finally, the SERS probe was redispersed in a solution containing 0.1 M NaCl, 10 mM PB, pH 7.4, with a final concentration of 0.1 nM. Before conducting SERS measurements, a certain amount of Raman tags (4-MBA) were needed to absorb on silver nanoparticles surface. Therefore, 30 μL 10 mM 4-MBA was added into a 600 μL 0.1 nM SERS probes solution, and the mixture was incubated for 2 h under gentle shaking. Then, the mixed solution above was centrifuged to remove excess 4-MBA and washed with 10 mM phosphate buffer (pH 7.4) for three times. The resulting product was suspended in a 100 μL of 10 mM sodium phosphate buffer in the presence of 0.3 M NaCl (pH 7.4) for further use. Fabrication of DNA-Encoded AgNPs modified oPADs. The first step to construct such DNA-encoded AgNPs modified oPADs is to build channels onto the paper surface with designed patterns using a wax printer. To maintain the capillary flow, channels were designed with a diameter of 1 mm and a length of 2 cm. The second important step is the baking stage. The wax-printed paper was heated on a hot plate at 110 °C for 2 min to melt the wax and interpenetrate through the paper. The heating temperature at the baking stage is of critical importance because the wax patterns on the paper would deform under high temperature over 130 °C. Subsequently, the wax-patterned paper was cooled to room temperature within just 1 or 2 min. As such, hydrophobic patterns were formed and hydrophilic channels were obtained using this method. The whole wax-printing process was completed in 10 min. Then, DNA-encoded AgNPs modified oPADs were constructed after adding 10−50 μL SERS probes solution into the certain regions of wax-patterned paper and dried naturally (Figure S4a). The detailed folding sequence to assemble an oPAD is illustrated in Figure S4b.45,46 SERS Analysis Using oPADs. First, all analyte solutions (DNA or miRNA) were dissolved in 10 mM phosphate buffer

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EXPERIMENTAL SECTION Materials and Apparatus. All oligonucleotides were provided by Sangon Biotech Co. Ltd. (Shanghai) with standard desalting and without further purification. The sequences of the oligonucleotides used in this work are listed in Table S1. All the chemicals were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise stated. All aqueous solutions were prepared using deionized (DI) water with a resistivity of 18.2 MΩ cm−1 from a Millipore system. The 100 nm spherical silver nanoparticles dispersed in phosphate buffer (2 mM, pH 7.4) was purchased from NanoComposix, San Diego, CA. UV−vis analysis was conducted using Cary 60 UV−vis (Agilent Technologies, America). TEM images were taken on a JEM-2100F (JEOL, FEI, Japan). The spray wax printer was Color Qube 8580 (Xerox, America). Raman spectra were acquired using a DXR intelligent Raman spectrometer equipped with an internal microscope (Thermo Scientific, America). Objectives with magnification of 10× (NA = 0.7) was used, and a 780 nm HeNe laser was used as the excitation source. Preparation of Ag Cubic Seeds. Silver cubic seeds were prepared according to previously reported protocol.43 The typical procedure is as follows: 20 mL of ethylene glycol was added into a 100 mL flask and preheated to 150 °C under magnetic stirring in an oil bath. Other reagents were also dissolved in ethylene glycol and dropped into the flask in sequence: 250 μL of NaHS solution (3 mM) was first added; after 2 min, 2 mL of HCl (3 mM) was added; followed by the addition of 5 mL of PVP55 (20 mg/mL). Subsequently, 1.5 mL of CF3COOAg solution (282 mM) was added after another 2 min. During the entire process, the flask was capped with a glass stopper except during the addition of reagents. Quench the reaction using an ice−water bath when the suspension had reached a brown color with a major LSPR peak around 435 nm. After centrifugation and washing once with acetone and twice with DI water, the resulting 40 nm cubic Ag seeds were obtained and redispersed in ethylene glycol for further use. The B

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Analytical Chemistry (PB) with 1 M NaCl and 20 mM MgCl2 (pH 7.4) (PB buffer is formulated from RNase-free water). To avoid RNA degradation, the experiment was carried out as much as possible on ice. Then 20 μL analyte solutions were injected into the four inlets at the top of oPADs. In order to ensure the liquid phase reaction, the oPADs were placed in a humidity box at room temperature for 15 min. In liquid environment, the analyte fluids hybridized with the preloaded SERS probes on the detection reservoirs of oPADs. The fast hybridization was realized due to capillary effect between cellulose fibers in wet paper. Finally, a 780 nm HeNe laser was used as the excitation source to focus on the detection reservoirs under the wet conditions for SERS assay.

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RESULTS AND DISCUSSION Figure 1 illustrates the working principle of a miRNA sandwich assay based on selective turning on of the SERS effect on DNA-

Figure 1. Schematic illustration of a miRNA sandwich assay based on a target-dependent, sequence-specific DNA hybridization assembly of Raman-active AgNPs.

Figure 2. Fabrication and characterization of DNA-encoded AgNPs modified oPADs. (a) Representative TEM images of AgNPs grown from Ag seeds in the presence of A10, T10, C10, G10 and 100 nm spherical AgNP. The corresponding 3D models are shown as insets. Scale bars: 50 nm. (b) SERS spectra of 4-MBA from different AgNPs (Ag-A10, Ag-T10, and Ag-G10), Ag cubic seeds, and spherical-like silver nanoparticle of 100 nm size. (c) SERS intensities of the 1587 cm−1 peak of 4-MBA from different AgNPs, Ag cubic seeds, and sphericallike silver nanoparticle of 100 nm size. The error bars were obtained from parallel assays of ten spots. (d) UV−vis spectra of bare Ag-C10, DNA probe functionalized Ag-C10, and DNA probe functionalized AgC10 hybridized with 100 nM TDNA in a sandwich assay. (e) SERS spectra of 4-MBA from Ag-C10 loaded Si and paper substrates with and without the addition of 100 nM TDNA.

encoded Raman-active anisotropic AgNPs through a targetdependent, sequence-specific DNA hybridization assembly, in which the drastic amplification in SERS stems from hot spot nanojunctions between closely coupled AgNPs. It is wellknown that optical properties of noble metal nanostructures are strongly correlated with their morphologies. In order to maximize the electromagnetic enhancement, at the outset we sought to synthesize AgNPs with various morphologies. Previous work by Lu et al. has demonstrated that DNA can serve as a useful tool to tailor the morphologies of AgNPs, in which the shapes of synthesized AgNPs were strongly influenced by the binding affinity of each of the bases and the DNA secondary structures.44 As a result, their SERS activities can also be regulated in a DNA sequence-dependent manner. On the basic of these findings, we used 10-mer oligoA, -T, -C, and -G to tune morphologies of AgNPs grown from Ag cubic seeds so as to mediate their SERS performances. As shown in Figure S1, the original shape of Ag seeds was cubic, with an average size of 40 nm. Then, 10-mer oligo-A, -T, -C, and -G were introduced into the mixture of Ag nanocubes as seeds, silver acetate as the precursor, and L-ascorbic acid as a reductant to modulate the morphology of AgNPs (the resulting AgNPs were referred to as Ag-A10, Ag-T10, Ag-C10, and Ag-G10, respectively). As shown in Figure 2a, both Ag-A10 and Ag-T10 exhibited similar truncated stellated octahedra morphology and referred to as truncated octahedra in this work, whereas Ag-C10 displayed a truncated tetrahedra shape and Ag-G10 remained cubic. The morphologies of these obtained AgNPs were consistent with the previous work.44 In addition, the average

sizes for Ag-A10, Ag-T10 and Ag-C10 were determined to be ∼86, ∼73, and ∼96 nm, respectively (Figure S2). Among them, Ag-C10 exhibited a relatively larger size distribution, which was consistent with the broader SPR band observed in Figure S3. Taken together, these results indicated that the morphologies of AgNPs grown from Ag seeds can be mediated by different DNA sequences. Noble metal NPs are known to display morphologydependent optical properties,47−50 we next evaluated SERS properties of AgNPs grown from Ag seeds in the presence of different DNA sequences. Here, 4-mercaptobenzoic acid (4MBA) was preadsorbed on the surfaces of AgNPs and served as a Raman tag. The representative SERS spectra are displayed in Figure 2b. We note that the excellent signal-to-noise ratio of the spectra confirms the high enhancement which can be obtained from intraparticle crevices. Distinct vibrational modes of MBA are clearly observed at ∼1080 cm−1 (νring‑7a, i.e., νring‑S) and ∼1587 cm−1 (νring‑8b, i.e., νC−C−C).51 Figure 2c compares SERS performances of different AgNPs (Ag-A10, Ag-T10, and Ag-G10) using the integrated intensities of the 1587 cm−1 peak, which suggested morphology-dependent SERS activities, with truncated Ag-C10 showing the highest SERS enhancement.44 As shown in Figure 2 (panels b and c), at 780 nm, Ag-C10 exhibited a relatively higher enhancement than spherical-like silver nanoparticle of the same size (ca. 100 nm), owing to the presence of multiple hot spots from the branching of Ag-C10 compared with spherical-like silver nanoparticle.52 As a result, truncated Ag-C10 was used for future experiments. C

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Analytical Chemistry The excellent SERS properties of as-synthesized AgNPs enable us to develop a SERS-based bioassay platform. As schematically illustrated in Figure 1, SERS probes were initially constructed by modifying batches of AgNPs with probe A and probe B, respectively. A minute red shift of ∼15 nm of SPR band was observed (Figure 2d), verifying the adsorption of DNA probes onto AgNPs surfaces. The functionalized AgNPs were then allowed to adsorb onto a single sheet of flat paper that has been wax-patterned with channels. A 3D paper analytical device was then assembled by folding the paper, designated as oPAD. The detailed fabrication process (Figure S4a) and the folding sequence (Figure S4b) are described in the Supporting Information. Following paper folding, the channels and reservoirs are properly aligned into a nine-layer device, enabling the access of analyte solution through the four inlets at the top of the device. The oPAD was then investigated for their SERS response using a synthetic target DNA (TDNA). The cooperative hybridization of probe sequences with the TDNA can effectively induce aggregation of AgNPs, as can be seen from the prominent red shift and broadening of SPR band in the extinction spectrum (Figure 2d). Hence, this assembly process can be achieved through a target-dependent, sequencespecific DNA hybridization. Figure 2e displays representative SERS spectra recorded in different circumstances. The Raman signals of MBA at 1080 and 1587 cm−1 drastically increased (typically 7−8 times at 1587 cm−1) when TDNA was added on paper or silicon substrate, which is attributed to the electromagnetic field amplification following the TDNA-led aggregation of SERS probes. The SERS intensity of the AgNPsloaded paper substrate is stronger (typically 1.5 times at 1587 cm−1) than that of the AgNPs-loaded silicon substrate. The excellent SERS performance is likely due to the 3D porous structure of paper substrate combined with abundant hydroxyl groups, which not only facilitates the fluid access but also provides a high surface area platform for the formation of highly active SERS substrate.53 The additional important advantages of using a paper substrate are low-cost, disposable, and ease of processability. Given highly precise and programmable self-assembly property of DNA hybridization combined with the simplicity of manufacturing our proposed device, our established oPAD holds enormous potential for bioassays. We then investigated the applicability of DNA-encoded AgNPs modified oPADs for quantitative SERS analysis of synthetic TDNA. Figure 3a displays SERS spectra of the sandwich complexes for various concentrations of the synthetic TDNA. As shown in Figure 3 (panels a and b), the SERS intensity increased monotonically with increasing the concentration of synthetic TDNA and showed a good nonlinear response over the range from 10−1 to 106 pM. The limit of detection (LOD) was 10−1 pM, indicating the high sensitivity of our DNA-encoded AgNPs modified oPADs. We then modified the probe DNA to fabricate oPADs for a sandwich miRNA assay. The miRNA extracted from has-miR-21 was selected as the target analyte. Similarly, we also observed a concomitant increase of SERS intensity with the increasing concentration of the miRNA with a LOD of 1 pM (Figure 3, panels c and d). Moreover, we evaluated the discriminatory power of miRNA assay by testing the fully complementary and mismatch target miRNA (hsa-miR-98 and has-let-7a have 91% similarities). As shown in Figure S5, the complementary target miRNA (hsa-miR-98) could be clearly differentiated from the mismatch target (has-let-7a), indicating that the oPADs could specifically recognize target miRNA. Having demonstrated the

Figure 3. DNA-encoded AgNPs modified oPADs for sensitive SERS analysis of synthetic TDNA and miRNA. SERS spectra of 4-MBA from Ag-C10 modified oPADs upon the addition of different concentrations of (a) synthetic TDNA and (c) miRNA, respectively. Plot of SERS intensities of the 1587 cm−1 peak of 4-MBA from Ag-C10 modified oPADs as a function of the concentrations of (b) synthetic TDNA and (d) miRNA, respectively. The error bars were obtained through the detection of ten parallel samples.

excellent biorecognition capabilities of DNA-encoded AgNPs modified oPADs, we then designed a nine-layer oPAD (Figure 4a and S6) for the simultaneous detection of has-miR-21, hasmiR-31, and has-miR-98. As shown in Figure 4a, the same colors corresponding to the accessible channels are interlinked. The analyte can be directed to flow through the designated channels and reservoirs. The detection reservoirs were

Figure 4. DNA-encoded AgNPs modified oPADs for miRNA assay. (a) Schematic illustration of the design of a nine-layer oPAD for multiplex detection with the detection reservoirs placed on the bottom layer. Note that different colors correspond to four analyte solutions: has-miR-21 (S1), has-miR-31 (S2), has-miR-98 (S3), and H2O (S4) as a control. The folding sequence is described in Figure S4b. (b) SERS spectra taken from each detection point reflect the selective enhancement through DNA hybridization. (c) SERS intensities of the 1587 cm−1 peak of 4-MBA from each detection point reflect the selectivity of oPADs for different miRNA assays. The error bars were obtained through the detection of ten parallel samples. D

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Figure 5. DNA-encoded AgNPs modified oPADs for multiplex miRNA assay. (a) Schematic illustration of the design of a nine-layer oPAD for multiplex detection. The folding sequence is described in detail in Figure S4b. The detection reservoirs were preloaded with four types of SERS probes. Specifically, miR-21 detection reservoirs: Ag-C10 modified with DNA probe 1 and probe 2; miR-31 detection reservoirs: Ag-C10 modified with DNA probe 3 and probe 4; miR-98 detection reservoirs: Ag-C10 modified with DNA probe 5 and probe 6; blank region as a control: only AgC10. (b) Schematic diagram of four unfold oPADs after injecting four samples through the four injection ports. Sample S5: hsa-miR-21 and has-miR31; sample S6: hsa-miR-31 and has-miR-98; sample S7: hsa-miR-21 and has-miR-98; sample S8: hsa-miR-21, hsa-miR-31, and has-miR-98. (c) Color-coded SERS intensity maps (based on the 1587 cm−1 peak) of sensing spots recorded from various samples (sample S5−S8). The error bars were obtained through the detection of ten parallel samples.

preloaded with SERS probe 1 (Ag-C10 modified with DNA probe 1 and probe 2), SERS probe 2 (Ag-C10 modified with DNA probe 3 and probe 4), and SERS probe 3 (Ag-C10 modified with DNA probe 5 and probe 6). The detailed sequences of probes and miRNAs are listed in (Table S1 and Table S2), respectively; the detailed information on locations of the detection reservoirs and compositions of SERS probes are described in (Figure S6). Then, four analyte solutions containing has-miR-21 (S1), has-miR-31 (S2), has-miR-98 (S3), and H2O (S4) as a control were injected into the four inlets at the top of oPAD. Finally, the SERS spectra were taken after 15 min of hybridization between analyte fluids and the preloaded SERS probes. As shown in Figure 3 (panels b and c), the oPADs demonstrated excellent selectivity owing to the intrinsic specificity of DNA hybridization assembly process that regulates the aggregation of SERS probes. For instance, only the addition of has-miR-21 induced the aggregation of SERS probe 1 and thus led to the significant amplification of Raman signals at 1080 and 1587 cm−1, whereas no enhanced Raman signals was observed for SERS probes 2 and 3. Note that all three specifically designed SERS probes for each miRNA demonstrated high selectivity with minimal off-target binding. We further investigated whether such a system could function as a multiplex detection platform in complex matrices. As shown in Figure 5a, the detection reservoirs were preloaded with SERS probe, and the detection reservoirs for hsa-miR-21, hsa-miR-31, and has-miR-98 were on different levels of the

device. A series of test samples (S5−S8) by dissolving different combinations of hsa-miR-21, hsa-miR-31, and has-miR-98 were measured. Four test samples were injected into the four inlets (marked with red arrows in Figure 5b), the samples flowed through the designated channels and reservoirs. After 15 min of hybridization between analyte fluids and the preloaded SERS probes. We then conducted the SERS analysis in which the measuring areas were marked with yellow arrows. The multiplex assay can then be directly read from the colorcoded SERS intensity maps (based on the 1587 cm−1 peak) recorded from sensing spots of four test samples (Figure 5c). Since every layer of the device in principle can be used for parallel SERS analysis of multiple analytes. This device can therefore be very useful for multiplexed detection and highthroughput screening. Taken together, these multiplex assay studies clearly indicated that our DNA-encoded AgNPs modified oPADs could potentially function as a rapid and sensitive device for multiplex bioassays.

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CONCLUSION We developed DNA-encoded Raman-active anisotropic AgNPs modified oPADs for rapid, highly sensitive and specific miRNA detection. There are several important aspects in the design and construction of such device that make it a promising sensor system for multiplex in vitro bioassays. First, the intricate network of fibrils within the hydrophilic paper substrate of oPADs can assist the formation of highly dense AgNP E

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aggregates, thereby contributing to the good sensitivity of assembled oPADs. Second, the sensing mechanism of oPADs relies on a target-dependent, sequence-specific DNA hybridization assembly of Raman-active AgNPs, which provides a highly generic and programmable tool for design bioassays with accuracy and predictability. Third, oPADs can be simply fabricated using a wax printer with low-cost and each layer can be used for parallel analysis of multiple analytes. Given these advantages, our established oPADs can thus serve as a promising sensor system for multiplex in vitro bioassays and clinical diagnostics.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.analchem.7b01861. TEM image and size distribution of Ag cubic seeds, size distributions and UV−vis spectra of Ag-A10, Ag-T10, and Ag-C10, detailed fabrication process and folding sequence, SERS spectra and histogram of specific analysis for fully complementary and mismatch target miRNA, detailed information on locations of detection reservoirs and compositions of SERS probes, sequences of probes, and miRNAs (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (+86) 021-54345484. ORCID

Lihua Wang: 0000-0002-6198-7561 Shiping Song: 0000-0002-0791-8012 Hao Pei: 0000-0002-6885-6708 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Shanghai Pujiang Talent Project (15PJ1401800 and 16PJ1402700); the National Science Foundation of China (Grant 21722502, 21505045, 21705048); China Postdoctoral Science Foundation (2015M581565 and 2017T100283); Ministry of Science and Technology of China (no. 2016YFA0201200); Key Research Program of Frontier Sciences, the Chinese Academy of Sciences (Grant QYZDJSSW-SLH031). L.L. acknowledges the financial support from the “1000 Youth Talents Plan”.

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