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Construction of Supramolecular Nanoassembly for Responsive Antibacterial Elimination and Effective Bacterial Detection Qiaoying Li, Yuanhao Wu, Hongguang Lu, Xinshi Wu, Shuai Chen, Nan Song, Ying-Wei Yang, and Hui Gao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b00873 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on March 1, 2017

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ACS Applied Materials & Interfaces

Construction of Supramolecular Nanoassembly for Responsive Antibacterial Elimination and Effective Bacterial Detection Qiaoying Li, † Yuanhao Wu, † Hongguang Lu, † Xinshi Wu, † Shuai Chen, † Nan Song, ‡ Ying-Wei Yang,*,‡ Hui Gao*,† † School of Chemistry and Chemical Engineering, School of Material Science and Engineering, Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, Tianjin University of Technology, No.391, West Binshui Road, Tianjin 300384, China ‡ International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China Keywords: antibacterial materials, supramolecular nanoassembly, aggregation-induced emission, bacterial detection, controllable antibacterial activity

ABSTRACT: There is an urgent need for developing novel strategies for bacterial detection and inhibition. Herein, a multifunctional nanomaterial based on mesoporous silica nanoparticles (MSNs) is designed, loaded with amoxicillin (AMO), and surface-coated with 1,2-ethanediamine (EDA)-modified polyglycerol methacrylate (PGEDA), cucurbit[7]uril (CB[7]), and tetraphenylethylene carboxylate derivatives (TPE-(COOH)4) by layer-by-layer (LbL) self-assembly technique. When bacteria contacts with this nanoassembly, the binding of anionic bacterial surface toward the cationic PGEDA layer of this material can reduce or break the interactions between PGEDA layer and TPE-(COOH)4 layer, ACS Paragon Plus Environment

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leading to attenuated TPE-(COOH)4 emission due to the weakening of aggregation-induced emission (AIE) effect. Furthermore, upon adding adamantaneamine (AD), the more stable AD⊂CB[7] complex forms and PGEDA is liberated through competitive replacement, thus leading to the release of AMO and resulting in much higher antibacterial ability of this nanomaterial. This newly designed nanomaterial possesses dual functions of controllable antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, and bacterial detection ability in aqueous media, suggesting that the design of this multifunctional antibacterial material will provide a simple, effective, and rapid way to control the activity of antimicrobial and open up an alternative new avenue for bacterial detection and elimination.

Introduction Nowadays, contamination by bacteria is one of the challenges to human life associated sectors, such as food, water, medical treatment, healthcare, and environment. The infections and diseases produced by harmful microorganisms cause health problems and even death for millions of people worldwide. Thus, there is an urgent need to develop new antimicrobial agents to detect and combat with microbes in water and biological fluids. In recent years, inorganic nanoparticles,1 quaternary ammonium salts,2 reactiveoxygen-species-generating conjugated polymers,3 antimicrobial peptides,4 and cationic polymers5,

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have been extensively studied for their applications especially in the fields of materials science, biology and biomedical science. Among these, cationic polymers, in particular, have various beneficial features, such as sustained inhibitory effect, broad-spectrum antibacterial feature, and easy to be functionalized through covalent or non-covalent approaches,8,

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owing to their remarkable capability for

disintegration of bacterial cytoplasmic membranes. However, they also showed cytotoxicity to human cells and caused hemolysis.11 To circumvent the undesirable cytotoxicity of cationic polymers, we take advantage of the supramolecular assembly of bis-aminated polymer with cucurbit[7]uril (CB[7]), a hollow pumpkinshaped macrocyclic molecule composed of 7 glycoluril units, with a hydrophilic exterior and ACS Paragon Plus Environment

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hydrophobic cavity, that has been widely employed in many research areas because of its ability to construct stable complexes interact with lots of guest molecules.12, 13 Typically, CB[7] binds strongly to cationic guests (typically ammonium cations) with a binding constant of 107–1017 M-1, through synergistic effect of ion-dipole interactions, hydrogen bonds and hydrophobic effect.14 Recently, Rotello et al. exploited nanoparticle assembly formed by diaminohexane-terminated gold nanoparticles and CB[7], and used adamantaneamine (AD) to remove CB[7] from the nanoparticle outer layer to activate the cytotoxicity of the amine-tethered gold nanoparticles and thereby caused cell death.15 In addition, Wang et al. manipulated a supramolecular antibiotic to reversibly switch-on and switch-off biocidal activity on demand by reversible assembly and disassembly process.16 Herein, we would like to use CB[7] to form a noncovalent complex with bis-aminated polymer in order to reduce the toxicity of this polymer. While upon adding AD, a more stable complex, that is, AD⊂CB[7], could form through competitive binding,17 thus the biocidal activity of polymer is exposed. On the other hand, there are various available methods for bacteria detection, such as specimen culturing, polymerase chain reaction (PCR), and target-specific immunoassays.18 But they often require long incubation duration for bacteria growth or complicated procedure and expensive apparatus. Therefore, rapid, simple and sensitive bacteria detection is highly desirable. Some new methods on the basis of surface enhanced Raman scattering (SERS), diagnostic magnetic resonance (MR), colorimetric and fluorescent imaging techniques have been investigated by means of some specific ligand receptor interactions such as antibody-antigen recognitions.19, 20 However, in many cases, the probes modified with specific recognition moieties do not work well because many types of microorganisms may have not been identified. Significantly, the fluorescence-based techniques have been widely used as fluorescent probes due to their high sensitivity, easy operation and low background noise over other methods.21 Recently, fluorescent materials with a unique phenomenon of aggregation-induced emission (AIE) was discovered by Tang et al., which are non-emissive or only show faint emission in good solvent but exhibit enhanced emission upon aggregation.22,

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As one representative AIE material,

tetraphenylethylene (TPE) and its derivatives have been applied in biological research, such as cell and ACS Paragon Plus Environment

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bacterial imaging, cancer therapy, and drug delivery.24 Tang et al. developed a new TPE derivative for bacterial susceptibility evaluation and high-throughput antibiotics screening.25 Liu et al. designed polyion complex micelles from negatively charged TPE sulfonate derivatives and cationic polyelectrolyte, which exhibit the AIE effect. After contacting with bacteria, the polyion complex nanosystem disrupts due to competitive binding of polyelectrolyte with negatively charged bacterial surfaces, leading to a conspicuous decrease of TPE fluorescence intensity.26 These promising results encourage us to use TPE derivatives in the current layer-by-layer (LBL) system for bacterial detection. Antibacterial nanoparticles have attracted great attention because of their low cytotoxicity, superior biocompatibility, high antibacterial efficency.27-31 Previous research showed that self-assembly on the surfaces of mesoporous silica nanoparticles (MSN) was an efficient processing method for the development of nanomaterials for good antibacterial efficiency.11,

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Herein, we report a new

nanoassembly constructed from amoxicillin (AMO), MSN, 1,2-ethanediamine (EDA)-modified polyglycerol methacrylate (PGEDA),36,

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CB[7], and TPE-based tetracarboxylic acid, namely TPE-

(COOH)4, for controllable antibacterial activity and bacterial detection (Scheme 1). We firstly load AMO into the mesopores of MSNs, then use CB[7] to interact with PGEDA to form stable supramolecular polymers on the surface of MSNs via ion-dipole interactions. Negatively charged TPE(COOH)4 can further bind with positively charged supramolecular polymers on MSN surface via electrostatic interactions to form a LbL supramolecular nanoassembly. In the presence of bacteria, the competitive binding of negatively charged bacterial surface to the positively charged PGEDA of LbL nanoassembly will lead to the quenching of fluorescence emission due to the loss of AIE effect of TPE. Significantly, upon adding AD, a more stable inclusion complex, i.e., AD⊂CB[7], forms and PGEDA is liberated through competitive replacement, thus leading to the release of AMO and much higher antibacterial ability of nanoassembly.

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Scheme 1. Schematic representation of nanoassembly and possible antimicrobial mechanism for bacterial detection and controllable inhibition. Experimental Section Preparation of MSN-AMO. MSN was synthesized according to our published procedure (See Supporting Information for details).11 MSN (15 mg) was added into an aqueous solution of AMO (15 mg). After stirring at room temperature for 2 days, the nanoparticles were obtained by centrifuged and washed once by ultrapure water. The product was obtained and named as AMO-MSN. To determine the loading efficiency, the amount of AMO in the supernatant was calculated by measuring the UV−vis absorbance at the wavelength of 275 nm. The AMO loading efficiency of MSNs was calculated according to (Equation 1) our previous work.11


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Loading capacity ሺ%w/wሻ=

Mass of loaded guest ×100% Mass of nanoparticles

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(Equation 1)

LBL Assembly. PGEDA (25 mg) was dissolved in PBS solution (pH=7.4, 5 mL). AMO-MSN (15 mg) was first added into PGEDA solution and shaken at 200 rpm at room temperature for 4 h, followed by rinsing with deionized water for 3 times to give MSN-PGEDA. Then the MSN-PGEDA was dispersed into PBS (pH=7.4, 5 mL) solution of CB[7] (5 mg mL-1). The mixture was sonicated and stirred for 2 h, followed by washing with ultrapure water 3 times and then lyophilized, to obtain MSNPGEDA-CB[7] nanoassembly. Then, to obtain the nanoassembly at varying TPE/MSN-PGEDA-CB[7] mass ratios (1:20, 1:10, 1:5, 1:2.5, 1:1), the PBS solutions (pH = 7.4) of TPE-(COOH)4 at various concentrations (2.5, 5, 10, 20, or 50 mg mL-1) were prepared. The MSN-PGEDA-CB[7] nanoparticles (50 mg) were resuspended into PBS solutions (pH = 7.4) of TPE-(COOH)4 and stirred for 0.5 h, followed by washing twice with PBS (pH = 7.4, 5 mL) for 2 min. After lyophilizing, the final product, MSN-PGEDA-CB[7]-TPE, was obtained. Unless special declaration, the obtained products were all loaded AMO, and the TPE/MSN-PGEDA-CB[7] mass ratio was 1:20. Controlled release of AMO. The release behaviour of the loaded AMO from the nanoassembly was investigated. AD (1.87mg, 0.01mM) and heparin sodium (4 mg) were dissolved in aqueous solution (2 mL), followed by adding the MSN-PGEDA-CB[7] (5 mg). The mixture was shaken at 150 rpm at 37°C. At every designated interval, aqueous solutions (4 mL) were taken out and fresh deionized water (4 mL) was added to the shaken incubator. The concentration of AMO was monitored by measuring the UV−vis absorption spectroscopy at the wavelength of 275 nm. The percentage of the total AMO released from the nanoassembly was obtained and plotted as a function of time. The nanoparticles without loading AMO were used as a negative control. The cumulative AMO released was calculated according to the equation (Equation 2) below: Cumulative AMO release (%) = Mt/M∞ × 100%

(Equation 2)

Bacteria Culturing. A single colony of E. coli (Gram-negative) and S. aureus (Gram-positive) on a ACS Paragon Plus Environment

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solid Luria-Bertani (LB) agar plate was transferred to liquid LB culture medium (5 mL) and grown at 37 °C overnight. The concentrations of bacteria were determined by measuring optical density at λ = 600 nm (OD600 of 1.0 corresponded to a concentration of 109 CFU mL-1). Determination of Minimum Inhibitory Concentration. Antimicrobial activities of nanoassembly were investigated using S. aureus and E. coli by broth microdilution methods. Briefly, nanoassembly was dispersed in deionized water and diluted from 518 to 2 µg mL-1 by a series of two-fold dilutions using nutrient broth. The bacterial suspension was then diluted 1000-fold step-wise, to obtain a final concentration of 105 CFU mL−1. The diluted bacterial solution (100 µL) and nanoassembly suspension (1 mL) with varied concentration was incubated at 37 °C in tubes for 16 h, respectively. After incubation, the bacterial viability was determined by measuring the absorbance by UV at 600 nm. We defined the MIC values as the lowest sample concentration at which more than 90% bacteria was inhibited. Broth containing bacteria alone was used as a negative control, and all tests were performed in three replicates. Colony assay. The antibacterial activity was investigated using a spread plate method. The bacteria were precipitated and re-suspended in 1 mL PBS solution in glass tubes with an OD600 of 0.01, which corresponds to the concentration of about 107 CFU mL-1. And then the nanoassembly MSN-PGEDACB[7]-TPE with or without AD were added to the bacterial suspension, respectively. These tubes were shaken at 200 rpm in incubators at 37 °C. Then the bacterial suspensions were taken out and diluted with an appropriate dilution factor. A 100 µL portion of the dilution with bacteria was transferred to the solid LB agar plate, followed by incubating at 37 °C for 16 h. The number of the colony-forming units (CFUs) was counted and the bacterial viability rates were determined. Fluorescence Microscopic Observations. Around 109 CFU of bacteria were harvested by centrifugation at 8000 rpm for 3 min, washed three times with PBS (pH = 7.4), and resuspended in 1 mL of PBS solution. The bacteria were treated with 300 µL of MSN-PGEDA-CB[7]-TPE (1 mg mL-1) for 10 min. To take fluorescence images, a drop of suspension was transferred to glass slide followed by ACS Paragon Plus Environment

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covering with another coverslip. The image was acquired with fluorescence microscope using 40× objective, using a high pressure Hg lamp for excitation (λex = 330 nm and λem = 480 nm). The untreated nanoassembly were used as a control. Bacterial imaging experiment. The bacteria were incubated at 37 °C overnight to a concentration of 109 colony forming units. Then the bacteria was harvested by centrifugation and resuspended in PBS (pH = 7.4). Then the bacterial suspension alone or treated with nanoassembly with or without AD were shaken at 200 rpm at 37 °C for 4h, followed by centrifuged at 8000 rpm for 3 min and washed three times with PBS (pH = 7.4). 2.5% glutaraldehyde was added to fix the bacteria for 4 h at room temperature. Then the bacteria were further washed twice with PBS solution, and dehydrated using a graded series of ethanol solution (30%, 50%, 70%, 85%, 95% and 100% for 20 min) and followed by being replaced by isopentyl acetate. The samples were dropped on silicon slice, allowed to air dry for SEM analysis. Fluorescent Spectra Measurements. The bacteria incubated overnight at 37 °C were harvested by centrifuging at 8000 rpm for 3 min and washed with PBS for three times. Then the cells were resuspended in PBS and diluted to different concentration as stock solutions. The final TPE-(COOH)4 concentrations in the nanoassembly solutions were adjusted to ~8 µM in all cases. 0.5 mL bacterial solutions were mixed with 0.5 mL of nanoassembly solutions to achieve predetermined bacterial concentrations. After incubation for 5 min at room temperature, the fluorescent spectra were measured. Results and Discussion Design and characterization of MSN-PGEDA-CB[7]-TPE. Controlled release systems of drugs and biological agents based on various materials, capable of selectively releasing cargo under different external stimuli, have been explored and applied in a variety of biological fields, such as antimicrobial, tumor therapy, and clinical diagnosis.38, 39, 40 Among them, MSNs have been widely employed in the construction of controlled release systems due to their size controllability, chemical stability, good ACS Paragon Plus Environment

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biocompatibility, and so on.41, 42, 43, 44 We reported biocompatible LbL coated MSNs (LbL-MSNs) that are designed and crafted to release encapsulated anticancer drug, by changing the pH or by adding competitive agents.45, 46, 47 Herein, we have designed and craft supramolecular polymer coatings on the surface of MSNs as controlled antibacterial systems via LbL self-assembly technology. The MSNs were prepared and AMO was loaded into MSN mesopores according to our previous report.11 The MSNs were soaked in a solution of AMO in water for 3 days. The amount of AMO loaded was monitored by measuring the UV absorbance at 275 nm, and was determined to be 11.2%. AMO, as a small molecule, is easy to be loaded into the mesopores of MSNs and quickly released from the mesopores of MSNs without any gating layers. Therefore, we designed an LBL strategy for better control of the AMO release and bacteria detection. After loading AMO within MSNs, the first layer was coated onto the negatively charged MSN surface with the positively charged PGEDA by means of electrostatic interactions. And then CB[7] was assembled with PGEDA by dint of host−guest interactions. Finally, negatively charged TPE-(COOH)4 was coated onto the nanoassembly by electrostatic interactions. Then, the formation of nanoassembly, as well as morphology and size of nanoassembly were monitored by SEM (Figure S1) and TEM (Figure 1). The shape of MSN samples were spherical, with an average particle diameter of approximately 125 ± 10 nm as determined by TEM (Figure 1a), whose hydrodynamic diameter was 190 ± 16 nm with a zeta potential of –27.0 mV (Table 1) as determined by DLS (Figure 2a). After loading with AMO and coating with PGEDA, the average particle diameter increased to 142 ± 12 nm (Figure 1b), meanwhile, the hydrodynamic diameter was 253 ± 57 nm (Figure 2b-c). Accordingly, the zeta potential of MSNs-PGEDA became + 31.3 mV due to the positive nature of PGEDA, indicating the successful assembling of polymer on the MSNs (Table 1). Finally, the average particle diameters of MSN-PGEDA-CB[7] and MSN-PGEDA-CB[7]TPE were determined to be 158 ± 17 and 161 ± 7 nm, respectively (Figure 1c, d), which was in good agreement with those obtained from DLS (Figure 2d, e), and the potential turned to be + 30.9 mV and + 23.8 mV after further coating with CB[7] and TPE-(COOH)4 (Table 1), respectively. The coating of neutral CB[7] did not change the zeta potential while the addition of slight amount of TPE-(COOH)4 ACS Paragon Plus Environment

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kept the positive charge of particle surface for better approach of bacteria. X-ray diffractions (XRD) were carried out to detect the state of crystalline of AMO before and after encapsulation. According to Figure 3a, the XRD spectra of free AMO exhibited complicated characteristic peak of AMO itself while the XRD spectra of MSN exhibited only single peak. After loading AMO into MSNs, the characteristic peaks of AMO disappeared. The small-angle XRD patterns of MSN and MSN-PGEDA-CB[7] exhibited a well-defined nature (Figure 3b), which agreed with the hexagonal symmetry of MSN. These results showed that AMO-loaded nanoassembly was successfully obtained.

Figure 1. TEM images of (a) MSN, (b) MSN-PGEDA, (c) MSN-PGEDA-CB[7], and (d) MSNPGEDA-CB[7]-TPE. ACS Paragon Plus Environment

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Figure 2. The hydrodynamic diameters and distributions of (a) MSN, (b) MSN-AMO, (c) MSNPGEDA, (d) MSN-PGEDA-CB[7], and (e) MSN-PGEDA-CB[7]-TPE as determined by DLS. Table 1. ξ-potential of MSN, MSN-PGEDA, MSN-PGEDA-CB[7], and MSN-PGEDA-CB[7]-TPE. Samples MSN MSN-PGEDA MSN-PGEDA-CB[7] MSN-PGEDA-CB[7]-TPE

Zeta-potential [mV] -27.0 +31.3 +30.9 +23.8


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In addition, we used FT-IR spectroscopy to monitor the LbL self-assembly of nanomaterials (Figure 3c). The spectroscopy of MSN-PGEDA-CB[7] displayed an obvious C=O vibration band at around 1750 cm-1 in its FTIR spectrum. Afterwards, the absorption peak at around 1790 cm-1 in the sample MSN-PGEDA-CB[7]-TPE could be attributed to C=O stretching of the carboxyl groups contained within TPE-(COOH)4. There was no new chemical bond formation during loading and selfassembly; the corresponding absorptions of all the materials were observed in the FT-IR spectra of nanoparticles. The FT-IR spectra suggested the successful LBL assembly on MSN. Thermogravimetric analysis (TGA) curves of MSN, MSN-PGEDA, and MSN-PGEDA-CB[7] were shown in Figure 3d. The amount of each layer adsorbed compared with MSN was defined by the weight loss. For MSN, the loss of 20% of weights between 25 °C and 1000 °C can be attributed to the removal of carboxyl groups of MSN. As for MSN-PGEDA, the weight loss increased to 35%, indicating that the weight percentage of PGEDA was about 15%. After assembled with CB[7], the weight percentage increased to 45%, and the extra 10% can be attributed to the weight percentage of CB[7]. The weight percentage of TPE-(COOH)4 was determined to be about 4.1% by measuring the UV absorbance at 330 nm. The controlled release of AMO from MSN-PGEDA-CB[7]-TPE nanoassembly was obtained by measuring the UV absorbance of AMO at 275nm. AMO could be released from the nanoassembly with the addition of AD compared with the control without AD addition (Figure 4). AD possesses a much higher binding affinity (Ka = 4.2 × 1012 M−1) toward CB[7] via host-guest interaction. As a consequence, an accelerate release of the cargo molecules was observed caused by the AD-induced dethreading of the CB[7] rings from the LbL self-assembly coatings, disassociation of supramolecular multilayers and the specific cleavage of MSN-PGEDA-CB[7]-TPE. Therefore, CB[7] plays a crucial role in regulating the release of AMO.


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Figure 3. (a) The XRD of AMO, MSN-AMO, MSN-PGEDA, MSN-PGEDA-CB[7], and MSNPGEDA-CB[7]-TPE. (b) The small-angle XRD of MSN and MSN-PGEDA-CB[7]-TPE. (c) FT-IR spectra of CB[7], MSN-PGEDA-CB[7], TPE, and MSN-PGEDA-CB[7]-TPE. (d) TGA curves recorded for MSN, MSN-PGEDA, and MSN-PGEDA-CB[7]. Fluorometric bacteria detection by MSN-PGEDA-CB[7]-TPE. The PBS solution of MSN-PGEDACB[7]-TPE showed an absorption maximum at 323 nm (Figure S2), corresponding to the maximum absorption of TPE-(COOH)4. The emission intensity of TPE-(COOH)4 gradually increases with increasing feed ratios of MSN-PGEDA-CB[7]/TPE, indicating the AIE property of TPE molecule resulting from the restriction of intra-molecular rotation of TPE via electrostatic interactions after LbL assembly (Figure S3). We believe competitive electrostatic interactions will also result in fluorescence change in our system. To verify this hypothesis, the bacteria-sensing capability and antimicrobial activity of nanoassembly were then investigated. MSN-PGEDA-CB[7]-TPE was used to detect the ACS Paragon Plus Environment

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bacteria and monitor the antimicrobial activity of the antimicrobial reagent through the fluorescence changes. The former was indicated by fluorescence spectroscopy based on the hypothesis that the binding of anionic bacterial surface to cationic PGEDA moieties could compete with TPE-(COOH)4, leading to attenuated TPE-(COOH)4 emission due to the weakening of AIE effect. As shown in Figure 5a, b, the emission intensity of nanoassembly weakens instantly after treatment with E. coli. As expected, the fluorescence intensity of the nanoassembly became much weaker after incubation with more E. coli. After treatment with 108 CFU/ mL of E. coli cells, ~50% loss in emission intensity can be observed. If we define the detection limit as the E. coli concentration at which 10% fluorescence intensity decrease (I480) could be measured, the detection limit was 2.5 × 106 CFU/mL for E. coli. The fluorescence quenching by S. aureus could be clearly observed by inverted fluorescence microscopy (Figure 5c, d). To explore the versatility of the multifunctional nanosystem based on MSN-PGEDA-CB[7]-TPE, we also used S. aureus, a Gram-positive bacteria strain, to test the variation of the fluorescence. As shown in Figure 6a, b, the emission intensity of nanoassembly was recorded after treatment with varying concentrations of S. aureus. The emission intensity weakens instantly with increasing S. aureus concentrations. After treated with S. aureus at a concentration of 108 CFU mL-1, the emission intensity decreased by ~75% and the detection limit was determined to be 5 × 106 CFU mL-1, which is much higher than that for E. coli. The higher detection limit and weaker emission intensity change against S. aureus cells could be attributed to insufficient surface charge on S. aureus.26 The fluorescence intensity change was also investigated by inverted fluorescence microscopy observations (Figure 6c, d). A realtime detection of the bacteria could be achieved by turn-down of the fluorescence. The fluorescence intensity of nanoassembly was weakened upon contacting with bacteria indicated that the noncovalent binding between MSN-PGEDA-CB[7]-TPE and bacteria is responsible for the observed weakened fluorescence emission. These results implied that TPE-(COOH)4 was replaced by anionic bacteria and disperse in PBS (pH = 7.4) solution, leading to weakened AIE effect. ACS Paragon Plus Environment

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Figure 4. Release profile of AMO from MSN-PGEDA-CB[7]-TPE in the presence (a) and absence (b) of AD.

Figure 5. (a) Fluorescence spectra and (b) the normalized fluorescence intensities recorded at λem = 480 nm for nanoassembly (λex = 330 nm) in the presence of varying concentrations of E. coli. The concentration of TPE-(COOH)4 was 15 µM for bacteria detection. (c) Fluorescent photographs recorded under UV irradiation via inverted fluorescence microscopy for aqueous dispersion of nanoassembly with and (d) without E. coli. ACS Paragon Plus Environment

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Antibacterial activity of MSN-PGEDA-CB[7]-TPE. The antibacterial activity of MSN-PGEDACB[7]-TPE with or without AD was investigated by growth inhibition of E. coli and S. aureus with varied concentrations of the nanoassembly. After incubation 16 h, their opticle density was measured by UV at 600 nm (OD600nm). AD has no obvious influence on the growth of bacterial cells.16 The MIC of nanoassembly with AD toward S. aureus was estimated to be ~125 µg mL-1 correspondingly, which was much lower than that of nanoassembly alone (Table 2). Similarly, there was a significant E. coli inhibition effect of nanoassembly in the presence of AD. These results suggest that the antibacterial activity can be controlled by AD addition. In the presence of AD, CB[7] disassociated from the nanoassembly due to the stronger interaction of AD-CB[7] than PGEDA-CB[7]. Amino group of PGEDA was then exposed to the bacteria membrane, which enhanced the antibacterial activity. Additionally, the disassociation of CB[7] also resulted in the release of AMO (Figure 4) , which was further attributed to the higher antibacterial ability of nanoassembly.

Figure 6. (a) Fluorescence spectra and (b) the normalized fluorescence intensities recorded at λem = 480 nm for nanoassembly (λex = 330 nm) in the presence of varying concentrations of S. aureus. The concentration of TPE-(COOH)4 was 15 µM for bacteria detection. Fluorescent photographs recorded ACS Paragon Plus Environment

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under UV irradiation via inverted fluorescence microscopy for aqueous dispersion of nanoassembly (c) with and (d) without S. aureus. Table 2. MIC against E. coli and S. aureus cells and expressed as the nanoassembly concentration with and without AD. S. aureus

MIC [µg/ml] >1000 125

MSN-PGEDA-CB[7]-TPE MSN-PGEDA-CB[7]-TPE+AD

E. coli MSN-PGEDA-CB[7]-TPE MSN-PGEDA-CB[7]-TPE+AD

MIC [µg/ml] >1000 250

Figure 7. Colony forming units (CFU) for S. aureus and E. coli treated with nanoassembly before and after addition of AD on LB agar plate. ACS Paragon Plus Environment

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A further demonstration of sustained antibacterial performance of nanoassembly with and without AD was conducted by means of evaluating its inhibition of bacteria growth. The antibacterial activities of nanoassembly toward E. coli and S. aureus were further explored. MSN-PGEDA-CB[7]-TPE with AD exhibited high killing efficiency (99%) towards E.coli, while killing efficiency less than 30% was obtained for MSN-PGEDA-CB[7]-TPE alone. Moreover, MSN-PGEDA-CB[7]-TPE with AD also exhibited high killing efficiency (99%) towards S. aureus, while killing efficiency was about 68% in the absent of AD (Figure 7). These results demonstrated that the antibacterial ability of nanoassembly is regulated by simple supramolecular dis-assembly process. SEM was performed to visualize the morphological change of E. coli and S. aureus treated by MSNPGEDA-CB[7]-TPE with and without AD. To visualize the difference of bacteria before and after treatment, the bacteria without any treatment were imaged as a negative control (Figure 8a, d). For MSN-PGEDA-CB[7]-TPE alone, the bacteria have clear edges and surface integrity because of the prevention of the insertion of amine groups into bacterial membrane (Figure 8c, f). Upon disassembling MSN-PGEDA-CB[7]-TPE by AD, the bacterial membrane morphology exhibits shrunk and fusion (Figure 8b, e), suggesting that the antibacterial activity possibly caused by distortion of the bacteria membrane of the interaction with disassociated MSN-PGEDA-CB[7]-TPE. These results verify again that the antibacterial ability is controllable. Finally, the biocompatibility and cytotoxicity of antimicrobial nanoassembly fibroblasts L929 were evaluated by CCK-8 assay. The cell viability of MSN-PGEDA was ∼68% when the concentration of MSN-PGEDA was 500 µg mL-1. Interestingly, there is no obvious cytotoxicity of MSN-PGEDA-CB[7]TPE to fibroblasts L929 cells even when the concentration increased to 500 µg mL-1 (Figure 9). The attenuated cationic groups in the LBL assembly were helpful for enhanced biocompatibility. Therefore, the nanoassembly exhibited very low cytotoxicity.


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Figure 8. SEM images of E. coli (a, b, c) and S. aureus (d, e, f) treated with PBS (a, d) and nanoassembly in the presence of AD (b, e) and nanoassembly in the absence of AD (c, f).

Figure 9. Cell viability assay of Fibroblasts L929 treated with MSN-PGEDA, MSN-PGEDA-CB[7], MSN-PGEDA-CB[7]-TPE in the absence of AD, and MSN-PGEDA-CB[7]-TPE in the presence of AD (0-500 µg mL-1).


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Conclusion In conclusion, we have successfully constructed a novel nanoassembly integrated with controllable antibacterial activity and bacterial detection via LBL assembly. By adding AD, the antibacterial activity switched on due to the dis-assembly of PGEDA and CB[7], and the release of AMO. This method is simple, effective, and rapid because any chemical modification on the active site of existing antibiotic is not required. Meanwhile, competitive electrostatic binding of negatively charged bacteria surface with PGEDA led to the decrease of TPE fluorescence emission intensity due to the weakening of AIE effect. The fluorometric assay showed a detection limit of 2.5 × 106 CFU mL-1 against E. coli. This easyobtained, multifunctional material is supposed to exhibit wide application for antibacterial and bacterial detection. ASSOCIATED CONTENT Supporting Information Some experimental section including the preparation of MSN, TPE-(COOH)4, cytotoxicity assay, hemolysis assay and the SEM studies, UV-Vis absorbance spectra of nanoassembly. The file are available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author * Y.-W. Yang, Email: [email protected] * H. Gao, Tel: (+ 86) 2260214259, E-mail: [email protected], [email protected] Notes The authors declare no competing financial interest. Acknowledgements The authors thank the National Natural Science Foundation of China (21374079, 21674080, ACS Paragon Plus Environment

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