CoreâShell Gold Nanorod@Layered Double Hydroxide Nanomaterial

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Biological and Medical Applications of Materials and Interfaces

A Core-shell Gold Nanorod@Layered Double Hydroxide Nanomaterial with High Efficient Photothermal Conversion and its Application in Antibacterial and Tumor Therapy Kun Ma, Yawen Li, Zhenguo Wang, Yuzhi Chen, Xin Zhang, Chunyuan Chen, Hao Yu, Jia Huang, Zhiying Yang, Xuefei Wang, and Zhuo Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b10373 • Publication Date (Web): 24 Jul 2019 Downloaded from pubs.acs.org on July 24, 2019

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ACS Applied Materials & Interfaces

A Core-shell Gold Nanorod@Layered Double Hydroxide

Nanomaterial

with

High

Efficient

Photothermal Conversion and its Application in Antibacterial and Tumor Therapy Kun Ma,‡[1] Yawen Li,‡[1] Zhenguo Wang [1] Yuzhi Chen,[1] Xin Zhang,[1] Chunyuan Chen,[1] Hao Yu,[1] Jia Huang,[2] Zhiying Yang,*[2] Xuefei Wang,*[3] Zhuo Wang*[1] 1

State Key Laboratory of Chemical Resource Engineering, Beijing Advanced Innovation Center

for Soft Matter Science and Engineering, College of Chemistry, Beijing University of Chemical Technology, North Third Ring Road 15, Chaoyang District, Beijing, 100029, China 2

Department of Hepatobiliary Surgery, Department of Gastroenterology, China-Japan Friendship

Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China 3

School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences,

Beijing 100049, China ‡

These authors contributed equally to this work.

* Correspondence: [email protected] (Zhuo Wang) [email protected] (Xuefei Wang) [email protected] (Zhiying Yang)

ACS Paragon Plus Environment

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ABSTRACT: Photothermal conversion efficiency (η) of gold nanorods (GNRs) can be tuned by enlarging the aspect ratio and forming core-shell structure. Herein, an easy synthesis method is developed to construct core-shell GNR@LDH nanostructure with GNRs and layered double hydroxides (LDHs). The interaction between Au and LDHs results some electron deficiency on the surface of Au and the more electrons induce more thermal energy conversion. The η value of GNR@LDH can reach up to 60% under the 808 nm laser irradiation, which is a significant enhanced conversion efficiency compared with the reported gold nanorods-based PTT materials. CTAB (cetyltrimethyl ammonium bromide) can be replaced totally during the synthesis process, and GNRs keep a good dispersion in LDHs. This core-shell composite GNR@LDH can be applied in photothermal antibacterial, tumor therapy and biological imaging with low dosage and nontoxicity.

KEYWORDS: gold nanorods; layered double hydroxides; photothermal conversion; antibacterial; tumor therapy INTRODUCTION In 2003, the initiated photothermal therapy (PTT) for cancer by gold nanoparticles are published.1 With the development of nanotechnology, various morphology gold nanomaterials are synthesized and the photothermal profile is improved. And they are gradually used in the fields of antibacterial, antitumor and other bio-application.2-4 Among the new materials, gold nanorods (GNRs) are applied widely in PTT on the basis of their good photothermal conversion efficiency. Decay of the plasmon resonances in GNRs through thermalization with the lattice generates heat, which can induce the raising of the surround temperature obviously. GNRs have been explored for a wide range of biological and biomedical applications.5-10 Gold nanorod has


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strong absorption in the range of 600-900 nm, and their molar extinction coefficients are higher compared with other plasmonic metallic nanoparticles, carbon materials, semiconducting nanomaterials, and organic nanomaterials in the first bio-window (700-980 nm).11 The high photothermal conversion ability of materials can bring better curative effect, and need less dosage for PTT with less toxicity. The photothermal conversion efficiency is relative with the absorption cross-section. For GNRs, the absorption cross-section can be tuned by enlarging the aspect ratio and covering silica or other materials to forming core-shell structure.12,13 However, the improvement of photothermal conversion efficiency for GNRs is not very significant. Another problem is that CTAB (cetyltrimethyl ammonium bromide) has obvious toxicity and is widely used for stabilization of GNRs. The effective stabilization of GNRs and clearance of CTAB is highly challenging when GNRs are used in biological fields. Recently, some semiconductor nanomaterials are explored with high photothermal conversion efficiency (η). Quasi-metallic WO2.9 nanorods shows good anticancer photothermal therapy with a 44.9% photothermal conversion efficiency under NIR irradiation.14 Bismuth Sulfide (Bi2S3)Gold (Au) heterojunction nanorods has a higher photothermal conversion efficiency (51.06%) than Bi2S3 without Au doping (33.58%).15 The improved photothermal conversion ability of these compounds depends on the artificial manufacturing defect of these nanoscale rods. Besides, to improve performance and control the morphology, constructing Au nanoparticles with two or three dimensional materials become more increasingly.16,17 Herein, we design a new core-shell GNRs covered by layered double hydroxides (LDHs) named as GNR@LDH, and its η value can reach up to 60% under the 808 nm laser irradiation, which shows the distinct high photothermal conversion efficiency among the reported gold nanorods-based PPT materials. The interaction between Au and LDHs results some electron deficiency on the surface of Au and the more


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electrons induce more thermal energy conversion. LDHs limit the Brownian motion of GNRs and heat energy is saved, which is also contribute to improve the temperature like an amber structure. CTAB shows serious cytotoxic and can disrupt cell membranes.18 Therefore, many alternative compounds are used to replace CTAB for avoiding the toxicity of CTAB. These molecules include poly(ethylene glycol) (PEGs), phosphatidylcholine, poly(sodium 4-styrenesulfonate) (PSS), inorganic mesoporous silica (mSiO2), calcium phosphate, and titanium dioxide (TiO2). The above materials show some cytotoxicity more or less.19 The residual of CTAB is one of the reasons to cause the toxicity of modified GNRs. LDHs are two-dimension nano/micro materials, and have been studied for more than centenary.20,21 LDHs are constructed with two metallic hydroxides, where defects can be easily caused under induction.22,23 And their typical character is that the nanoscale two-dimensional laminates are arranged longitudinally in order to form a three-dimensional crystal structure. LDHs are synthesized by mineral salts in water. The starting materials are economic, and the solvent is green. LDHs have high surface area, showing almost no biological toxicity, and have been applied in drug delivery, antitumor and the immobilization of biomacromolecules.24-29 Herein, we develop an easy one-pot synthesis method to construct core-shell GNR@LDH nanomaterials, which can replace CTAB totally and get a well-dispersed gold nanorods with excellent photothermal conversion ability. This core-shell composite can be applied in photothermal antibacterial, tumor therapy and biological imaging with low dosage and almost no cytotoxicity. RESULT AND DISCUSSION


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Figure 1. (A) Synthesis scheme of GNR@LDH. (B) Powder of GNR@LDH. (C) Solution of GNR@LDH. (D) TEM image of GNRs. (E) TEM image of GNR@LDH. (F) SEM image of GNR@LDH. (G, H, I, J) HAADF-STEM images and elemental mapping of GNR@LDH. (K) Extinction spectra of GNR@LDH, GNR-LDH, GNR and LDH. (L) XANES spectra at Au Kedge for GNR@LDH, GNR-LDH and Au foil. (M) Fourier-transform EXAFS spectra at Auedge for GNR@LDH, GNR-LDH and Au foil. (N) The optimized structure diagram of GNR@LDH. (O) XRD patterns of LDH and GNR@LDH. GNR@LDH is synthesized by using GNRs as seeds to promote the formation of Mg-Al LDH crystallization surround GNRs (Figure 1A). GNRs are synthesized using a binary surfactant mixture including sodium oleate (NaOL) and CTAB. GNR@LDH is structured with an easy one-pot synthesis method at 60 °C for 6 hours. GNR@LDH can be dried to powder (Figure 1B) for storage, and can be re-dispersed well in water with red color (Figure 1C). Figure 1D shows the average length of GNRs is ~60 nm and the aspect ratio is 4:1. The 4:1 aspect ratio of GNRs always shows good absorption in NIR range, good stability and gets through cell membrane easily.30,31 The average radius of core-shell GNR@LDH is about 200 nm (Figure 1E and 1F). GNR@LDH consists of MgAl-LDH nanosheet doped with GNRs. We construct another composite by only mixing LDHs and GNRs as a reference, and named as GNR-LDH. LDHs can adsorb some GNRs when they meet each other. The TEM images of GNR-LDH show that fewer GNRs are on the surface of LDHs (Figure S1). The element composition of GNR@LDH and GNR-LDH is analyzed by energy-dispersive spectroscopy (EDS) on HAADF-STEM and the elemental maps are shown in Figure 1G-J and Figure S1. EDS analysis data show that the mole ratio of Mg and Al in GNR@LDH and GNR-LDH is similar, which is consistent with mole ratio of MgAl-LDH (Figure S2). The quality ratio of Au in


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GNR@LDH is 10.1 %, and 5.9 % in GNR-LDH. There are more GNRs in GNR@LDH and the dispersion of GNRs is better than GNR-LDH. The stability of GNR@LDH in different medium is evaluated and the result is shown in Figure S4A. In order to maintain the good stability in biological environment, GNR@LDH is modified with polyethylene glycol (PEG).32 The PEGylation GNR@LDH (GNR@LDH-PEG) is stable in fetal bovine serum (FBS), water and phosphate buffer saline (PBS) for 24 hours. The DLS (dynamic light scattering) test is conducted to evaluate the size distribution of GNR@LDH. In Figure S4B, the peak of GNR@LDH-PEG is obviously narrower around 200-300 nm, while the peak of GNR@LDH (from 200-1000 nm) is much wider because of the aggregation of GNR@LDH. The FTIR spectra of GNR@LDH, PEG and GNR@LDH-PEG are shown in Figure S4C. The peaks at 2890, 1140, 1350, 1100 cm-1 show the stretching vibration of C-H, stretching vibration of C-C, bending vibration of C-H and stretching vibration of C-O, which indicates the structure of PEG. For GNR@LDH-PEG, PEG has been modified on the surface of GNR@LDH successfully. Due to the inherent profile of LDH, the long-time dispersion in aqueous media is still a challenge. In the further work, more trials are needed to improve the stability of LDH composites in water environment. The UV-vis spectra shows that GNR had a typical LSPR (localized surface plasmon resonance) absorption peak at the near infrared region (800~900 nm), meanwhile LDH has an all-band absorption. GNR@LDH exhibits a stronger absorption than GNRs (Figure 1K). Compared with GNR, a little red-shifted LSPR peak of GNR@LDH is observed. From the morphology of GNR@LDH (Figure 1E), several GNRs are bounded together by LDH flakes. It may lead to the coupling of GNRs. This coupling actually is reflected in the longitudinal SPR band of GNR@LDH. It is broadened greatly compared with GNR (Figure 1K). The slight red-shift of the band may come from such coupling or the change of refractive index around the GNR due to


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LDH coating. Besides, this phenomenon may be also attributed to the charge variation of Au moiety in GNR@LDH. The electron deficiency on Au moiety induces the red shift of the plasmon adsorption, whereas the excess of electrons induces the blue shift.33 The red-shifted LSPR peak of GNR@LDH indicates that LDH may cause an excess electron deficiency on Au moiety. In order to character the electron transfer of the sample, Extended X-Ray Absorption Fine Structure (EXAFS) spectra and X-ray Absorption Near Edge Structure (XANES) spectra of GNR@LDH are recorded by the synchrotron radiation. In Figure 1L, the increased energy of the white line indicates the enhancement of Au oxidation state. The white line is around 11922 eV (from 11920 to 11925 eV). The GNR@LDH exhibits a stronger white line compared with Au foil (Au0). Moreover, its absorption edge shifts to lower photon energy, which is also consistent with the redshift of GNR@LDH UV-vis absorption. This indicates a low electron density on supported Au, and the electron transfer from Au nanorod to the shell. In Figure 1M, the Au-Au FT-EXAFS spectra of GNR@LDH is weaker than GNR-LDH and Au foil, which indicates the decrease of the Au-Au bonding number. The Au-Au bond length of GNR@LDH (~2.48Å) has an apparently decrease compared with Au foil (~2.58Å), which indicates the strong Au-LDH bonding in GNR@LDH composite.34,35 This may be due to the more interaction of Au and oxygen atom in LDH in GNR@LDH composite, which is the reason to result electron deficiency and red shift of the absorption spectra of GNR as shown in Figure 1K. XAFS spectra confirm that the redshift of GNR@LDH UV-vis absorption is due to the electron transfer between GNR and LDHs (The shift caused by electron deficiency was also reported by Ju33). The core-shell GNR@LDH has some more electron interaction with LDHs, while adsorbed GNR-LDH has weaker interaction. The optimized structure diagram of GNR@LDH processed by Materials Studio 6.1 is shown in Figure 1N. The diffraction pattern of GNR@LDH (Figure 1O, curve b)


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shows that Au phase (JCPDS card 99-0056) is doped in MgAl-LDH, and the typical peaks of MgAl-LDH keep well. The (003), (006), (012), (015), (018), (110) and (113) reflections of MgAl-LDH present the high crystallinity of GNR@LDH.

Figure 2. Cytotoxicity assessment of GNR@LDH. (A) FTIR spectra of CTAB, LDH-CTAB (washed by DI water and ethanol respectively), LDH and GNR@LDH. (B) Cytotoxicity of GNR with

various

coatings

including

organic

poly(sodium

4-styrenesulfonate)

(PSS),

poly(ethyleneglycol) (PEG) and inorganic mesoporous silica (mSiO2), dense silica (dSiO2), and


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LDH. (C) Hemolysis of GNR@LDH in different concentration. (D) UV-vis adsorption spectra of the supernatant after hemolysis assay. In order to get a good GNRs-based PTT material, we need to solve two problems: one is the stability of the material, and the other is the complete replacement of CTAB to ensure the biocompatibility in vivo. When CTAB protected GNRs are dried to powder, they aggregates totally and cannot be re-dispersed in water again. GNR@LDH can be synthesized in mass, dried to powder and re-dispersed well in water again (Figure 1B, C). The solid immobilization of GNRs by LDHs makes them dispersible whenever in solid state or in aqueous ambient. We record and compare the Fourier transform infrared (FTIR) spectra of CTAB, LDH-CTAB and GNR@LDH (Figure 2A). There are two strong peaks at 2920 cm-1 and 2850 cm-1, which are the peaks of methyl and methylene stretching vibrations of CTAB. These two peaks appear in GNRLDH but not in GNR@LDH. During the process of growing LDH around GNRs, CTAB is eliminated completely. The LC-MS (liquid chromatograph-mass spectrometer) analysis of GNR@LDH proves that CTAB are eliminated. The retention time of CTAB is 4.20 min. In the mass spectra at 4.20 min, the peak at the m/z of 284 is belong to CTAB. For the chromatogram of GNR@LDH, there is no peak at 4.20 min, which identifies that there is no CTAB left in GNR@LDH (Figure S3). We synthesized the GNRs with various chemical components, and compared their cytotoxicity by MTT methods (Figure 2B). GNR@LDH has almost no cytotoxicity, and the other GNRs (GNR@PEG, GNR@PSS, GNR@mSiO2 and GNR@dSiO2) have cytotoxicity more or less. The hemolysis assay of GNR@LDH is carried out with blood cells. As shown in Figure 2C, almost no signal can be detected at 541 nm compared with positive control group. The hemolysis percent is also calculated and the GNR@LDH presents a very low hemolysis percent in Figure 2D. The GNR@LDH is biocompatible and presents nearly nontoxic


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to live cells. GNRs have been synthesized and studied for decades, but few of them have robust stability and the CTAB cannot be eliminated totally.

Figure 3. Photothermal property of materials. (A) Temperature elevation of GNR@LDH (300 μg/mL), GNR-LDH (510 μg/mL), LDH (300 μg/mL), GNR (30 μg/mL) and PBS under 808 nm irradiation (2 W/cm2). (B) IR thermal images of GNR@LDH (300 μg/mL) irradiated by an 808 nm laser (2 W/cm2) from 0 min to 7 min. (C) Photothermal stability of GNR@LDH (300 μg/mL) irradiated by an 808 nm laser (2 W/cm2). The solution was irradiated 8 min and then cooled down to 30 °C, which was repeated 6 times. (D) Monitored temperature profile of GNR@LDH,


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GNR-LDH (300 μg/mL) and GNR (30 μg/mL) over 600 s irradiation by an 808 nm laser (2 W/cm2), followed by natural cooling after the laser was turned off. The photothermal conversion profile of GNR@LDH is investigated. After 10 min irradiation under 808 nm laser at the power of 2.0 W/cm2, the changed temperature (ΔT) of GNR@LDH solution (300 μg/mL, including about 30 μg/mL GNRs) reaches to 43.33 °C, and the final temperature can go beyond 70°C. ΔT of GNRs solution (30 μg/mL) is 31.80 °C, ΔT of GNRLDH solution (510 μg/mL, including about 30 ug/ mL GNRs) is 33.90 °C, ΔT of LDH solution (300 μg/mL) is 3.7 °C and ΔT of PBS is 5.3 °C (Figure 3A). GNR@LDH has a high photothermal conversion performance than GNRs and GNR-LDH. When the concentration of Au is set as the same, the photothermal conversion ability of GNR@LDH is better than GNRLDH. This can be contributed to their different structure and stability of GNR. The GNRs in GNR@LDH are trapped in LDH, while the GNRs in GNR-LDH are easily fall down because of the unstable absorption interaction. With the increased concentration of GNR@LDH, the temperature changes of the samples show the concentration dependent profile. In 10 min, the temperature can reach the platform (Figure S5A). The IR thermal images of GNR@LDH solution from 0 min to 7 min illustrate the increased temperature from 20 to 70°C (Figure 3B). GNR@LDH is irradiated by a 808 nm laser at the power of 2.0 W/cm2 for 10 min and then cooled for 10 min to room temperature. This process is repeated for six times. GNR@LDH has a good performance on photothermal stability (Figure 3C). The heating and cooling curve of GNR@LDH solution is measured in Figure 3D and the photothermal conversion efficiency (η) of GNR@LDH is calculated to be 60% (detailed in photothermal effect evaluation in Supporting Information). We go through η values of the reported GNRs-based PTT materials (e.g. Rose Bengal-GNR, GNR@polyacrylic acid/calcium phosphate), other inorganic (e.g. Au nanoshell,


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black phosphorus quantum dot, Au nanocups) and organic PTT materials (e.g. dopaminemelanin colloidal nanospheres, peptide-porphyrin Nanodots) (Table S2).14,15,36-40,50 GNR@LDH has a comparable photothermal conversion efficiency among these materials, especially among the reported gold nanorods-based materials. We suggest that there are two reasons for the high η of GNR@LDH. One is that LDHs limit the Brownian motion of the GNRs. For GNR@LDH, NIR-induced energy has less loss in kinetic energy and more energy is converted into heat energy under the irradiation, which results in a higher photothermal efficiency of GNR@LDH. The other reason is due to the increased deficiency of GNRs. In the EXAFS spectra (Figure 1M), the peak intensity of GNR@LDH is weaker than GNR-LDH and Au foil, which indicates the reduction of the Au-Au bonding. For GNR@LDH, the heterojunction of GNRs and LDHs composite results electron deficiency and red shift of the absorption spectra of GNRs (Figure 1K). The electron deficiency of GNRs can induce more electrons. Under NIR irradiation, more electrons can produce more phonons and release heat radiation resulting the enhanced photothermal conversion.


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Figure 4. Antibacterial activity evaluation of GNR@LDH-PEG. (A) Plate count method in different conditions for E. coli. (B) Survival rate of E. coli in corresponding group (n = 3). (C) Plate count method in different conditions for S. aureus. (D) Survival rate of S. aureus in corresponding group (n = 3). 0.005 < *P < 0.01, 0.001 < **P < 0.005, ***P < 0.001, compared


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with control group. (E) SEM figures of E. coli contacting with GNR@LDH under 3 minirradiation of 808 nm laser. (F) SEM figure of S. aureus contacting with GNR@LDH under 3 min-irradiation of 808 nm laser. As a good PTT material, GNR@LDH presents good photothermal conversion ability and biocompatibility compared with other functionalized GNRs (e.g. GNR@PEG, GNR@PSS, GNR@mSiO2 and GNR@dSiO2). GNR@LDH-PEG is applied in antibacterial, tumor imaging & treating, and the biosafety in vivo is checked. The antibacterial experiments for GNR@LDH PEG against E. coli and S. aureus are conducted by the plate count method (Figure 4A-4D). When the concentration exceeds 200 μg/mL, GNR@LDH-PEG exhibits a significant antibacterial effect in 3 minutes irradiation. Most bacteria are killed when the temperature rises to 55 °C.41,42 The sterilization rates of GNR@LDH-PEG for E.coli and S. aureus are 99.25% and 88.44% with the amount of 300 μg/mL (including 30 ug/mL Au) for 5 min irradiation. In the previous work, we find that LDHs can adhere many bacteria colonies, which is due to the positive charge surface of LDHs and high surface area.43 GNR@LDH also exhibits surface positive charge (Table S3), which is beneficial for adsorption of bacteria. Scanning electron microscopy (SEM) images of GNR@LDH-PEG and microbes explore that GNR@LDH-PEG can adsorb bacteria effectively, so GNR@LDH-PEG get closer with bacteria and enhance the antibacterial activity. Before irradiated by 808 nm laser, no obvious damage can be seen on the bacterial membrane of the rod-shaped E. coli and spherical S. aureus (Figure S6A and S6B). Under the irradiation, some crumbles occur on the surface of E. coli and the cell membrane become incomplete, distorted and even melted (Figure 4E, red arrow). For S. aureus, the membrane change is similar to that of E.coli (Figure 4F, red arrow). The leakage of cytoplasm carries away a large amount of cellular components including nucleic acids.44,45,46 Consequently,


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GNR@LDH-PEG has a good photothermal antibacterial activity on both Gram-positive and Gram-negative bacteria under a 808 nm light.


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Figure 5. Wound-healing experiment on mice. (A) The photographs of treatments with PBS (control), GNR-LDH-PEG and GNR@LDH-PEG for S. aureus induced wound infection on Day 0, 4, 6, 8, 11, 14. The dosage of GNR@LDH-PEG and GNR-LDH-PEG are both 50 μL, 300 μg/mL. Scale bar, 5 mm. (B) Diameter change of the wound area on Day 0, 4, 6, 8, 11, 14. (C) IR thermal images of wound infection mice during continuous irradiation treated with PBS, GNR-LDH-PEG and GNR@LDH-PEG. (D) Bacteria colonies formed by the S. aureus on wound area treated with GNR@LDH-PEG and GNR-LDH-PEG. (E) Survival rate of bacteria before and after treatment on the wound area (n = 3). (F) H&E staining slices of wound skin tissue treated with PBS, GNR-LDH-PEG and GNR@LDH-PEG on Day 2, 4, 8, 14. Scale bar, 100 μm. LDHs can promote the wound healing in mice due to the nutritious metal cations and nontoxicity.43 Upon that the wounds are infected by bacterial suspension of S. aureus with the concentration of 1 × 107 CFU/mL. The wound-bearing mice are divided into three groups: control group (using PBS), GNR-LDH-PEG group (GNR-LDH is dispersed with aid of PEG) and GNR@LDH-PEG group (GNR@LDH-PEG is dispersed with aid of PEG). The concentration of GNR@LDH-PEG and GNR-LDH-PEG solution are both 300 μg/mL (50 μL), while in previous reported work, more than millimolar dosage was needed to get antibacterial ability.43 The temperature of the wound treated with GNR@LDH-PEG can reach to 55 °C in 3 min, while the GNR-LDH-PEG group reaches to 42 °C and the control group is up to 40 °C. GNR@LDH-PEG exhibits good photothermal conversion performance in the body of the mice (Figure 5C). In Figure 5A, the mice treated with GNR@LDH-PEG recover faster than other groups and the statistical diameter change of the wound area is showed in Figure 5B. The number of bacteria colonies taken from the wound area before and after treatment is counted


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(Figure 5D and 5E). The sample treated by GNR@LDH-PEG shows less bacterial colonies. The wound skin tissues of the three group mice were obtained and stained by hematoxylin and eosin (H&E) on day 2, 4, 8, 14 (Figure 5F). Plenty of white blood cells were produced at the initial stage of infection and they mainly existed as neutrophils. Neutrophils (green arrows) appeared in all the three group after 2 days, demonstrating inflammation by S. aureus. Meanwhile, infected necrotic foci (red rectangles), which were diseased tissue with pathogenic microorganisms, were also produced, indicating the severe damage and infection of tissue. In the following days, neutrophils transformed to macrophage (blue arrows) surrounding by infected necrotic foci, which was responsible for cleaning up dead cell debris, damage tissue and pathogen. Meanwhile, the fibroblasts (black arrows) appeared, participating in the repair of tissue damage. For GNR@LDH-PEG group, macrophage and fibroblasts appears firstly. After 4 days, the congestion (black rectangles) and cell debris (yellow arrows) still existed in control group due to the serious inflammation. Granulation tissue (green rectangles) and fibroblasts (black arrows) can be seen in GNR@LDH-PEG group, which means the beginning of the wound healing. On day 8, the granulation tissue and the fibroblast appeared in control group. In the process of wound healing, squamous epithelium (yellow rectangles) forms during the healing process as a positive signal, and the macrophages disappear day by day. In GNR-LDH-PEG group on day 8, granulation tissue coexisted with squamous epithelium, while there were still many macrophages. In GNR@LDH-PEG group, almost all granulation tissues were covered with squamous epithelium, and macrophage disappeared. After 14 days, in control group, macrophage decreased clearly and new fibrous tissue was continuously regenerated in control group. Lots of foci were filled with granulation tissue. In GNR-LDH-PEG group, the squamous epithelium covered almost all granulation tissue. In GNR@LDH-PEG group, the foci almost disappear and the


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neonatal tissues are smooth. Simultaneously, a large number of intact capillaries filled with red blood cells appeared, proving that the treatment effect is excellent. Photothermal therapy with GNR@LDH-PEG at proper temperature can alleviate inflammation at the wound area and promote the skin generation. All of the healing signals appear earlier in GNR@LDH-PEG group than other groups, which promotes a faster healing process. The weight change of mice is recorded daily without major fluctuation (Figure S7). The blood analysis and liver function detection are analyzed (Figure S8 and Figure S9). The H&E-stained slices (Figure S10) of organs indicate that no organ damage occurs.


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Figure 6. In vivo photoacoustic imaging and CT imaging for tumor. (A) PA images of mice at different time after intravenous injection of GNR@LDH-PEG (200 μL, 200 μg/mL). Scale bar: 3 mm. (B) Intensity of PA signal in tumor after intravenous injection of GNR@LDH-PEG. Error bars represent standard deviation (n = 5). (C) CT images of the mouse with tumor before and after injection with GNR@LDH-PEG (100 μL, 80 mg/mL). (D) CT Value of GNR@LDH-PEG at different concentrations in solution. GNRs can be used for tumor imaging agent in photoacoustic and enhanced contrast CT agent. Dual-mode imaging including photoacoustic (PA) imaging and computed tomography (CT) imaging of GNR@LDH-PEG are conducted on tumor-bearing mice for illustration of the accumulation and penetration profiles. After the tail vein injection for 7 hours, PA signals was observed in the tumor site (red circle) due to the accumulation of GNR@LDH-PEG in the tumor site. After 12 hours, the signal decreased gradually and was almost metabolized after 24 hours (Figure 6A and Figure 6B). Apparent CT signal in tumor site can be seen after injection while no signal can be detected before injection (Figure 6C). The CT values standard curve of GNR@LDH-PEG is displayed in Figure 6D. On the basis of the PA/CT imaging results, GNR@LDH-PEG can penetrate into tumors and accumulate for more than 20 hours. Due to the enhanced permeability and retention (EPR) effect, the GNR@LDH-PEG nanoparticles are passively transported to the tumor site after intravenous injection.47 The nanoparticles have been modified by PEG, which will substantial increase the blood residence time. Because of the large specific surface area of GNR@LDH, the density of PEG on the surface of GNR@LDH is so high which leads to reduced plasma protein adsorption, opsonization and nonspecific uptake so that more particles will accumulate in tumor site.48 The EPR effect of nanoscale materials can induce the longer imaging time and better photothermal therapy in the future.


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Figure 7. Photothermal therapy for tumor. (A) Temperature of the tumor sites under irradiation (n = 5). (B) Tumor volume in different group (n = 5). The dosage of GNR@LDH-PEG and GNR-LDH-PEG are both 200 μL, 300 μg/mL. 0.005 < *P < 0.01, 0.001 < **P < 0.005, ***P < 0.001, compared with control group. (C) Photograph of tumors in different groups. a)


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GNR@LDH-PEG + 808 nm. b) GNR-LDH-PEG + 808 nm. c) GNR@LDH-PEG. d) GNRLDH-PEG. e) 808 nm. f) Control. (D) H&E staining of the heart, liver, spleen, lung, kidney tissue slices after 14-day tumor therapy experiment for the different groups. Scale bar, 200 μm. (E) Blood analysis for mice in different groups including white blood cell (WBC, 109 /L), red blood cell (RBC, 1012 /L), hemoglobin (HGB, 10 g/L), hematocrit (HCT, %), mean corpuscular volume (MCV, fL), mean corpuscular hemoglobin concentration (MCHC, 10 g/L), platelets (PLT, 1011 /L), mean platelet volume (MPV, fL), neutrophilic granulocyte (Gran, 109 /L). (F) Liver function detection for mice in different groups including alanine aminotransferase (ALT, U/L), aspartate aminotransferase (AST, U/L), alkaline phosphatase (ALP, U/L), albumin (ALB, g/L) and total protein (TP, g/L). The PTT performance of GNR@LDH-PEG for tumors is studied with HeLa cells. When the concentration of GNR@LDH-PEG is 300 μg/mL, the temperature of the solution maintains above more than 50 °C in 2 minutes and reaches to 60 °C finally, which induces the death of living cells (Figure S11). In the following PTT for tumor-bearing mice, the concentration of GNR@LDH-PEG is set to 300 μg/mL (30 μg/mL Au), equaling to 0.3 mg/kg Au in mouse, which is really a low dosage compared with the reported ones (3 mg/kg for the amount of Au).49 Temperature of the tumor sites under irradiation in different groups are recorded by IR camera (Figure 7A). The PTT materials are tail intravenous injection. In GNR@LDH-PEG (300 μg/mL, 200 μL, Au: 0.3 mg/kg) group, the temperature around the tumor raises from 28 °C to 50 °C within 2 min and maintains beyond 50 °C for 8 min, which guarantee to ablate the tumor effectively. For GNR-LDH-PEG treated group, the tumor can be ablated partly under the irradiation. The tumors treated with GNR-LDH-PEG has a much lower temperature elevation than GNR@LDH-PEG compared with temperature elevation in solution. The GNRs in GNR-


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LDH-PEG is just adsorbed on LDH, which is not as stable as GNR@LDH-PEG. When the GNR-LDH-PEG solution is injected intravenously, GNR-LDH-PEG circulates in the body and reach the tumor site. During the circulation, the GNRs in GNR-LDH-PEG are easy to be desorbed due the weak interaction with LDHs. While the GNRs in GNR@LDH-PEG remains stable. With the decrease of GNRs in GNR-LDH-PEG, the tumors treated with GNR-LDH-PEG showed a lower temperature. For in vitro experiment, the solution sample of GNR-LDH-PEG is stable without loss of GNRs compared to the in vivo circulation environment. So compared with Figure 3A, the GNR-LDH treated group in Figure 7A has a lower temperature elevation than GNR@LDH. For PBS and the groups without the irradiation, the tumors cannot be inhibited (Figure 7B). For the GNR@LDH-PEG-treated group, the temperature can reach more than 50 °C and keep it for a longer time, so GNR@LDH-PEG has a significant tumor ablation effect than the other control groups clearly. The tumor size of GNR@LDH-PEG group significantly reduces or even disappears in two weeks while the tumors in other groups become increasingly bigger than before (Figure 7C). The H&E-stained slices prove that GNR@LDH-PEG have no hazards to major organs including heart, liver, spleen, lung and kidney (Figure 7D). And the content in different organs is shown in Figure S13. 6.48% of GNR@LDH-PEG accumulated at the tumor site. Due to the local inflammation after treatment, the number of WBC and Gran in “GNR@LDH-PEG + 808 nm laser” group maintain a high level than other groups (Figure 7E). There no other obvious difference in blood analysis and liver function detection among the control and treated groups (Figure 7F). And the body weight of mice keeps well during the treatment process (Figure S12). CONCLUSION


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In summary, an easy synthesis method is developed to construct core-shell nanomaterials by using GNRs and LDHs. The synthesis procedure is simple and robust, the core-shell nanostructure of GNR@LDH ensures the well dispersion of GNRs even dried to power, and it can be re-dispersed in water without aggregation. GNR@LDH shows high photothermal conversion efficiency. The high photothermal conversion efficiency (60%) is mainly due to the limited movement of GNRs by LDHs and the increased defect of GNRs characterized by XANES and EXAFS. CTAB on the surface of GNRs can be replaced during the synthesis progress of GNR@LDH. The elimination of CTAB and the covered LDHs make the core-shell PTT material as a candidate for biological therapy and imaging. GNR@LDH-PEG is applied in antibacterial wound-healing, PA/CT imaging and tumor ablation. The results demonstrate that the GNR@LDH-PEG will be an integrated platform for diagnosis and therapy due to its dualmode imaging and good PTT performance. Due the high photothermal efficiency of GNR@LDH, the dosage of Au is low, which will be helpful for decreasing the toxicity and keeping biological safety in the future clinic application. ASSOCIATED CONTENT Supporting Information The Supporting Information is consist of experimental procedures, additional SEM, TEM, HAADF-STEM images, EDS analysis, LC-MS data, stability test, photothermal property test and comparison, Zeta potential, cell assay, weight and blood analysis for mice. AUTHOR INFORMATION Corresponding Author


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* Correspondence: [email protected] (Zhuo Wang) [email protected] (Xuefei Wang) [email protected] (Zhiying Yang) Author Contributions Conceptualization, Y. Li and K. Ma; Methodology, Y. Li; Investigation, Y. Li and K. Ma; Data Curation, K. Ma, Y. Li and Y. Chen; Writing-Original Draft, K. Ma; Writing-Review & Editing, Z. Wang and K. Ma; Funding Acquisition, Z. Wang; Supervision, Z. Wang; Resources, Jia Huang, Zhiying Yang and Hao Yu. K. Ma and Y. Li contributed equally to this work.

ACKNOWLEDGMENT We thank Ph.D Yingyi Liu for designing TOC figure. We are thankful for the supports from Natural Science Foundation of China (No. 21575032, 81728010, 21775010, 11811530639), the Beijing Natural Science Foundation (No. 7192106), Fundamental Research Funds for the Central Universities (PT1902, XK1901, XK1802-6), and the University of Chinese Academy of Sciences. REFERENCES 1. Hirsch, L. R.; Stafford, R. J.; Bankson, J. A.; Sershen, S. R.; Rivera, B.; Price, R. E.; Hazle, J. D.; Halas, N. J.; West, J. L. Nanoshell-mediated Near-infrared Thermal Therapy of Tumors under Magnetic Resonance Guidance. PNAS, 2003, 100, 13549-13554. 2. Huang, X.; Neretina, S.; El-Sayed, M. A. Gold Nanorods: From Synthesis and Properties to Biological and Biomedical Applications. Adv. Mater. 2009, 21, 4880-4910.


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