Upconversion Luminescence-Activated DNA Nanodevice for ATP

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Upconversion Luminescence-Activated DNA Nanodevice for ATP Sensing in Living Cells Jian Zhao, Jinhong Gao, Wenting Xue, Zhenghan Di, Hang Xing, Yi Lu, and Lele Li J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11161 • Publication Date (Web): 27 Dec 2017 Downloaded from http://pubs.acs.org on December 27, 2017

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Upconversion Luminescence-Activated DNA Nanodevice for ATP Sensing in Living Cells Jian Zhao,†,# Jinhong Gao,†,# Wenting Xue,† Zhenghan Di,† Hang Xing,‡ Yi Lu,§ and Lele Li*,† †

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China ‡ Institute of Chemical Biology and Nanomedicine, College of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan, 410082, China §

Departments of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States

Supporting Information Placeholder ABSTRACT: Designer DNA nanodevices have attracted extensive interest for detection of specific targets in living cells. However, it still remains a great challenge to construct DNA sensing devices that can be activated at desired time with a remotely applied stimulus. Here we report a rationally designed, synthetic DNA nanodevice that can detect ATP in living cells in a upconversion luminescence-activatable manner. The nanodevice consists of a UV light activatable aptamer probe and lanthanidedoped upconversion nanoparticles which acts as the nanotransducers to operate the device in response to NIR light. We demonstrate that the nanodevice not only enables efficient cellular delivery of the aptamer probe into live cells, but also allows the temporal control over its fluorescent sensing activity for ATP by NIR light irradiation in vitro and in vivo. Ultimately, with the availability of diverse aptamers selected in vitro, the DNA nanodevice platform will allow NIR-triggered sensing of various targets as well as modulation of biological functions in living systems.

Due to its unique programmable base-pairings, ease of synthesis, and biocompatibility, DNA is showing increasing promise for designing and engineering nanodevices and nanoprobes.1 The various DNA-based nanodevices were usually activated by specific molecules (e.g., small molecules, nucleic acids, and proteins) or by changes in their environment (e.g., pH, temperature), and then followed by reporting an output signal, releasing a cargo or performing other useful functions.2-5 Such stimuli-triggered DNA nanodevices are suitable to various applications including molecular sensing,3 controlled drug release,4 and programmable chemical synthesis.5 In particular, there is emerging development of DNAbased fluorescent nanodevices for sensing because the fluorescence readout can be recorded in real time and in situ.1a Despite the progress made, limited examples have been reported for the intracellular detection.3 In addition, typical DNA-based nanodevices for fluorescent sensing employ “always active" design where the probes are in “off” state and then are turned "on" in the presence of the targets.3 However, a major limitation for such intracellular sensing strategies is that the probes can be turned on during the cellular delivery and uptake process (e.g., bind with extracellular targets), before they reach the desired locations in cells, which lead to lack of detection accuracy and low signal-to-noise ratio. Therefore, there is a compelling need to

design new sensing device for tracking and imaging intracellular targets with high spatial and temporal resolution.1a Most recently, photoactivatable DNAzymes was developed by attaching photolabile groups to the nucleobases for intracellular sensing.6 However, such systems are limited to detection of metal ions. In addition, the use of high-energy UV light or photothermal effect for activation of the DNAzyme in such designs can harm the cells. Thus motivated, here we present for the first time the design, synthesis, and application of a near-infrared (NIR) light activated DNA nanodevice for sensing of biomolecules in living cells through the integration of aptamer-based lock design with photon upconversion technology. Such nanodevice allows the use of NIR light as an external regulatory tool, which is much more desirable than UV light because of its less photodamage and deeper penetration for remote activation of materials with relatively high precision and low interference.7 As an initial demonstration, we chose ATP, an indispensable molecule at the center of metabolism,8 as the target biomolecule to prove the feasibility of our design. Since the spatial and temporal dynamics of ATP significantly affect both intracellular and extracellular physiology, reliable ATP sensing with relatively high precision is of paramount importance for disease diagnosis.9 As illustrated in Figure 1, the nanodevice contains two dependent components as follows: UV light activatable DNA aptamer probe and lanthanide-doped upconversion nanoparticles (UCNPs). Inspired by structure-switching aptamers,10 an aptamer-based lock mechanism was designed to establish activatable aptamer probe. The aptamer strand was initially locked by a complementary DNA containing a photocleavable (PC) group, which can be denoted as “PC-inhibitor”. When the quencher-bearing PC-inhibitor hybridizes to the aptamer strand modified with a fluorophore Cy3, FRET occurred between Cy3 and quencher due to the close proximity of the two, leading to a low fluorescence signal background prior to sensing. In addition, the hybridization of PC-inhibitor and aptamer could prevent the aptamer from binding to ATP until the PC-inhibitor is photolyzed. Upon light irradiation, the PC group will undergo photolysis and generate short DNA fragments with greatly reduced binding affinity of the PC-inhibitor to the aptamer strand. In the presence of ATP, the aptamer will restore its capability to switch its structure to bind ATP, leading to the dissociation of the cleaved PC-inhibitor from the ATP aptamer strand and a dramatic increase in the fluorescent signal. Furthermore, UCNPs

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Figure 1. Working principle of NIR light activated DNA nanodevices for ATP sensing in living cells. (a) Schematic showing the UV light activatable ATP sensing mechanism of the aptamer based probe. (b) Design of DNA nanodevices based on the integration of the aptamer probe with upconversion nanotransducer for NIR activated intracellular ATP sensing. functioned as the NIR-to-UV nanotransducer to absorb NIR light and emit UV light locally for the temporal control over the photolysis of the PC group, thus realizing remote activation of the DNA probe in the deep-tissue-penetrable NIR window. UCNPs exhibit advantageous photoconversion ability to convert NIR light into tunable shorter-wavelength emissions spanning from UV to NIR regions.11 Although many studies have demonstrated the use of UCNPs as signaling unit for construction of fluorescent sensors,11c,k,l no attention has ever been focused on the use of UCNPs for design of NIR-activated sensing devices. The performance of the activatable aptamer probe was first examined in a HEPES buffer. The designed PC-inhibitor containing PC groups spaced ten nucleotides at the 5'-end, as well as the control strands that do not contain PC groups spaced part were hybridized to the aptamer strand to obtain Apt-Act and Apt-on probes, respectively (Figure 2a, inset). In the absence of 365 nm light, the fluorescence increased with increasing ATP concentrations in the case of the Apt-on probes only (Figure 2a). In contrast, no obvious increase in fluorescence was observed for Apt-Act probes, indicating the efficient inhibition of the sensing activity of the Apt-on probe by increasing the numbers of nucleotides of the complementary strands. In order to test whether the inhibition effect of the Apt-Act probe could be reversed through light activation, we used 365 nm light to irradiate samples of the Apt-Act probe for different time. No obvious change of the fluorescence was observed in the absence of light and after addition of ATP (Figure S1), while with a 365 nm irradiation (5 mW/cm2), followed by the addition of ATP (5 mM), an obvious increase in fluorescence intensity of Cy3 was observed (Figure 2b). Longer light exposure led to higher increase in the fluorescence, which peaked in 6 min (Figure 2b, inset). The results indicate that the sensing activity of the Apt-Act can be

Figure 2. Evaluation of the Apt-Act probe for its UV light activated sensing performance in solution. (a) Fluorescence spectra of the Apt-on and Act-Act probe responding to ATP at different concentrations, respectively. Inset: schematic showing their molecular structure. (b) Fluorescence spectra of the Apt-Act probe by increasing doses (in minutes) of 365 nm light, in response to 5 mM ATP. Inset shows corresponding effect of irradiation time on its fluorescence intensity. (c) Fluorescence titration curve of the Apt-Act probe for ATP upon the irradiation with 365 nm light. (d) Response of the probe to different nucleoside triphosphates with and without 365 nm light irradiation, [Analytes] = 5 mM. restored through light irradiation. As a control, a DNA strand with the same sequence as PC-inhibitor but without PC group (nonPC-inhibitor) was employed to hybridize to the aptamer strand. No change in fluorescence intensity was observed for this control probe (Apt-non) in the presence of ATP with or without light irradiation (Figure S2), proving that the Apt-non was neither active nor activatable for ATP sensing. We can conclude that the photolysis-mediated breakage of the PC bond was indispensable for the design of activatable sensor probe. The light-activated response of the Apt-Act to different concentrations of ATP was tested (Figure 2c). The Cy3 fluorescence intensity increased after light irradiation and subsequent addition of increasing concentrations of ATP. Of note, the intracellular ATP concentration (1−10 mM)4b falls nicely within this detection window. The selectivity of this Apt-Act probe toward ATP over other nucleoside triphosphates was also investigated. As shown in Figure 2d, addition of UTP, CTP or GTP induced little fluorescence change of the AptAct probe compared with ATP treatment under light irradiation, suggesting that the high selectivity of the aptamer probe was maintained for Apt-Act. To achieve high efficiency of NIR-to-UV upconversion luminescence (UCL), oleic acid (OA) capped hexagonal-phase NaGdF4:70%Yb,1%Tm@NaGdF4 core-shell UCNPs were synthesized with a thermal decomposition approach. In this NPs, Yb/Tm was co-doped in the core to realize ultraviolet and visible UCL from Tm3+ upon NIR excitation (Figure S3). Gd3+ sublattice is capable of transporting upconverted photonenergy from the core to the shell of the NPs, allowing the energy to be migrated to the NP’s surface (Figure S3).11h The core-shell design could also efficiently avoid surface quenching-induced energy loss of the active dopants (Yb/Tm) in the core and ensure high upconversion efficiency.11c Transmission electron microscopy (TEM) showed a uniform hexagonal plate-like shape of the UCNPs with an average size of ∼40 nm and a shell thickness of ∼5 nm (Figure S4). The core-shell structure was further confirmed by HAADF-STEMEDS elemental mapping and line scan (Figure S5). These

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Journal of the American Chemical Society of Mitotracker, implying that Apt-Act/UCNPs were mainly transported to endo/lysosomal compartments.

Figure 3. Characterization of the Apt-Act/UCNPs. (a) TEM and HRTEM (inset) image of the Apt-Act/UCNPs. (b) Upconversion luminescence spectra of the Apt-Act/UCNPs under excitation at 980 nm. Inset shows the photographs of the solution of AptAct/UCNPs under 980 nm laser illumination. hydrophobic nanocrystals were then converted into hydrophilic ones by removing OA on their surface, and then coating a cationic polymer, poly(d-lysine) (PDL), to facilitate subsequent loading of Apt-Act probes via electrostatic interactions. TEM image of the UCNPs loaded with Apt-Act probes (Apt-Act/UCNPs) show that they are monodispersed without change in shape (Figure 3a). The interplanar spacing of 0.52 nm in the HRTEM image (the inset in Figure 3a) was corresponding to the typical (100) plane of the hexagonal NaGdF4 structure. The surface density of DNA was estimated to be 30 probes per UCNP. The integration of Apt-Act probes on the UCNPs was further confirmed by dynamic-lightscattering analysis and zeta potential measurement at each step during the synthesis (Figure S6). The Apt-Act/UCNPs display characteristic Tm3+ dominated UV (320 nm and 360 nm) and visible blue (450 nm and 475 nm) UCL under excitation at 980 nm (Figures 3b, Figure S7), corresponding to the 3P6 → 3F4, 1D2 → 3H6, 1D2 → 3F4, and 1G4 → 3F4 transitions, respectively.11c Upon irradiation with 980 nm laser, the luminescence of the aqueous solution of Apt-Act/UCNPs appears blue in color (Figures 3b, inset). The NIR-to-UV UCL of the UCNPs makes it possible for the remote activation of the Apt-Act probes.

Figure 4. Intracellular colocalization of Apt-Act/UCNP nanodevices in HeLa cells. Confocal fluorescence images of HeLa cells pretreated with Apt-Act/UCNPs (only labeled with Cy3) and further stained with Mito-Tracker Green and Lyso-Tracker Green, respectively. Scale bar: 10 µm. We then evaluated the cellular internalization of the AptAct/UCNPs in HeLa cells using only Cy3 labeled Apt-Act (without labeling with quencher). When Apt-Act probes were incubated with cells for 2 h, no obvious fluorescence was observed in cells (Figure S8), indicating inefficient cellular uptake of naked DNA due to the electrostatic barrier of the cell membrane. Significantly, bright fluorescence signal was observed in the cells exposed to Apt-Act/UCNPs (Figure S8), indicating that integration with the UCNPs could facilitate cellular uptake of the Apt-Act probes. We next examined the distribution of Apt-Act/UCNPs (Apt-Act was only labeled with Cy3) inside cells (Figures 4). The imaging study showed that the fluorescence signal of AptAct/UCNPs colocalized well with that of Lysotracker but not that

Figure 5. NIR light activated imaging of ATP in live HeLa cells. Confocal fluorescence images of HeLa cells treated with (a) AptAct/UCNPs, (b) Apt-Act/UCNPs + NIR, (c) Apt-non/UCNPs, (d) Apt-non/UCNP + NIR. Scale bar: 10 µm. Finally, we evaluated the applicability of Apt-Act/UCNPs for NIR-activated imaging of ATP in living cells. The nanodevice was incubated with HeLa cells at 37 °C for 2 h, followed by NIR irradiation (980 nm, 1.2 W/cm2). A MTT assay was performed to evaluate the biocompatibility of Apt-Act/UCNPs, and no significant effects on cell viability under current condition was observed (Figure S9). As shown in Figure 5a and b, without NIR irradiation, fluorescence microscopy revealed minimal Cy3 fluorescent signal in the cells. In contrast, upon irradiation with a 980 nm laser, much stronger intracellular fluorescence was observed, suggesting the NIR activated effect of this system. Using the inactive Aptnon/UCNP nanoprobe, no significant enhancement of fluorescence signal was observed in the cells upon NIR irradiation (Figure 5c and d), confirming that the observed fluorescence increase for Apt-Act/UCNPs was due to the NIR-activated ATP sensing. To demonstrate the capability of Apt-Act/UCNPs to monitor ATP level changes inside cells, iodoacetic acid (IAA) was used to inhibit the ATP production of the cells.12 Compared to HeLa cells without incubation with IAA, the cells treated with IAA displayed an obvious decrease of fluorescence intensity for the NIRactivated ATP imaging (Figure S10), indicating that IAA treatment caused the intracellular ATP concentration drop out the detection window. As a control, Apt-non/UCNPs did not show any fluorescence response to the IAA treated cells with and without NIR irradiation (Figure S11). To further confirm the above results from confocal microscopy, we examined the whole cell population using flow cytometry. The analysis indicated that the intracellular fluorescence intensity of the cells treated with Apt-Act/UCNPs and NIR irradiation was 1.8-fold higher than that of cells exposed to Apt-Act/UCNPs without irradiation (Figure S12), while the Apt-non/UCNPs showed no obvious fluorescence change upon irradiation. Together, these results strongly validate the capacity of the nanodevice for temporal control of ATP imaging in living cells by UCL. The good performance of this nanodevice in living cells motivated us to further investigate its NIR-activated sensing in vivo. The nude mice bearing HeLa xenograft tumors were treated with Apt-Act/UCNPs or Apt-non/UCNPs (the DNA probes were

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This work was financially supported by NSFC (Nos. 21771044) and the Young Thousand Talented Program.

REFERENCES

Figure 6. NIR light activated ATP imaging in vivo. (a) Representative fluorescence images of HeLa tumor-bearing mice injected with Apt-Act/UCNPs without or with subsequent NIR irradiation at the tumor site. Arrows indicate the sites of tumors. (b) Effects of NIR irradiation on ATP sensor activity in tumor over time; data normalized to fluorescence signal at 0 h (data are medians ± quartiles, n = 4). *P < 0.05, **P < 0.01. labeled with Cy5 for in vivo imaging) then underwent intratumoral photoactivation by a 980 nm laser irradiation (1.2 W/cm2). As shown in Figure 6a, the mice treated with Apt-Act/UCNPs showed a remarkable enhancement of fluorescence signals in the tumor region both at 2 and 4 h after NIR irradiation, while no apparent fluorescence change was observed from the group without irradiation. Quantitative analysis showed that NIR irradiation after injection of Apt-Act/UCNPs resulted in 1.86- and 1.81-fold higher fluorescence at the tumor site than that in mice receiving Apt-Act/UCNPs without irradiation at 2 and 4 h, respectively (Figure 6b). In contrast, Apt-non/UCNPs showed similar intratumoral fluorescence intensity with and without irradiation (Figure S13). As another control, some crucial nucleotides of the aptamer strand in the Apt-Act/UCNPs are mutated to inactivate its ATP binding activity. NIR-activated ATP sensing was not observed for this system in vitro and in vivo (Figure S14). Taken together, it is conceivable that the Apt-Act/UCNP nanodevice could be applied for NIR-activated ATP imaging in living bodies. In conclusion, we have demonstrated a rationally designed DNA sensing system that permits spatiotemporal control by UCL. We believe that the UCL-activated sensing strategy introduced here can be generally applied to temporal controlled detection of various bio-targets, which will add to the toolbox of techniques for bioanalysis in living systems.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details and data (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected]

Author Contributions #

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J.Z. and J.G. contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

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