Editorial pubs.acs.org/journal/aidcbc
Nano Tools Pave the Way to New Solutions in Infectious Disease
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vaccine or potential exposure of a population to a given disease type. One of the enabling properties of nanomaterials is the unique range and tunability of size and composition-dependent electrical, optical, and magnetic properties. These nanomaterial properties can be highly enabling in the design of sensitive detection systems. One example is the use of giant magnetoresistive (GMR) nanosensors for immune monitoring. GMR nanosensors rely on the changes in electrical resistance based on minute changes in magnetic field; the Wang group1 utilized GMR nanosensors composed of nanometer thick layers of conducting and magnetic materials to generate an array which conjugated directly with families of linear peptides grown directly on the array. Magnetic nanoparticles bind to the array via antibody recognition in a sandwich assay, yielding small shifts in magnetic field that result in signal. The exquisite sensitivity of the assay was demonstrated in a nanosensor chip designed to measure auto-antibodies directly from human serum based on a series of known DNA histone modifications. The nanosensor array could detect differences in peptide sequence with resolution down to a single amino acid and recognized antibodies in the 1 to 100 picomolar range directly from serum. Because the assay is based on nanoparticle binding, it is possible to remove the bound species and fully regenerate the array for reuse multiple times. These qualities make the approach highly viable for point-of-care analysis of a patient immune state. On the other hand, Kurabayashi and co-workers2 investigates the use of plasmonics in place of more traditional fluorescent signal as the basis of a multiplexed cytokine immunoassay. Here, the concept is to provide tools for rapid, safe, and frequent monitoring of the immune state of patients during the course of disease, which would better inform physicians on treatment regimen and state of disease recovery, as well as potential autoimmune response. For such assays, very low volumes of blood should be used to enable frequent sampling even for small children and infants. To measure a range of different cytokine proteins, a microfluidic array based on the antibody conjugation and surface patterning of gold nanorods led to a 480 sensing spot multiplexed array. The resulting chip can measure cytokine concentrations down to 5 to 20 pg/mL using a serum sample of only 1 μL; 6 key cytokine concentrations were determined directly from a serum sample over a period of 40 min, making this method highly portable, readily stored, and simple and rapid to use on patients in a range of different medical and field care environments. Chan and co-authors3 have used the size dependent optical properties and narrow wavelength fluorescence of quantum dots (QDs) to create a QD Barcoding approach toward disease detection. Here, the idea is to use QDs as highly efficient, bright, and stable fluorophores that can be encapsulated into larger polystyrene microspheres. The polystyrene bead surfaces are then modified with a capture DNA strand that will bind to a
nfectious disease is one of the most critical problems facing the world, presenting several significant medical and technological challenges. The evolution of virulent new infectious agents, or ones that were formerly little known and contained, such as Zika and Chikungunya, or H1N1, has accelerated in recent years. Several known strains of bacteria responsible for common infections have evolved resistant strains that cannot be treated with today’s arsenal of antibiotics. The rate at which new antibiotic molecules can be developed is shadowed by the increase in resistant strains; furthermore, increased use of antibiotics generally leads to acquired resistance. There is a strong and rising need for the ability to detect and identify infections at early stages and provide treatment in a form that can kill infectious agents at high efficiencies, but will not risk human safety or the development of more resistant or virulent strains. Effective vaccines can help prevent the spread of infection and can in some cases effectively vanquish certain diseases from global communities. Unfortunately, there are several challenges in the identification of effective antigens, and the necessary level and type of activation of the immune system to promote long term protection. Nanoscience brings new tools and capabilities to every aspect of these challenges. Thanks to the ever-increasing convergence of biology, engineering, and medicine, there have been significant new advances and increased understanding in critical medical challenges such as cancer. However, there is a great deal more for the field to learn regarding how to utilize these capabilities, significant research, engagement, and translational activity for furthering the field. Addressing the issues of infectious disease is one of the next big frontiers for those who work on materials and approaches at the nanoscale. Although the number of researchers working at the interface between nanomaterials and infectious disease is small relative to those in cancer, regenerative medicine, and other areas, the potential for growth in the field is high. There are several research groups who have already been working on many of these significant challenges, representing areas from physics, chemistry, materials science, and chemical engineering as well as biology and biomedical engineering. This virtual issue celebrates the emergence of a now quickly growing field by looking at examples taken from just the past 2 years of ACS Nano and our newer sister journal, ACS Infectious Diseases. In this array of examples, we have tried to cover different areas of impact for Nano in this burgeoning field, including the design of materials for immune monitoring and pathogen and disease detection, systems enabling to vaccine development, and nanomaterials development for the treatment of infection, from blood-borne disease to the penetration of bacterial biofilms.
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DETECTION Monitoring of the immune and/or disease state can provide a means of much more rapid response to infectious disease outbreak, methods to indicate autoimmune or infection states in humans, and a method of determining the efficacy of a © 2017 American Chemical Society
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and the challenges that nanomaterials can help to address in building immunity against disease. The review provides an overview of the influence of particle size, shape, and charge and the different mechanisms by which particle delivery systems may influence the immune response. Dendritic cells (DCs) are the target for a number of nanoparticle strategies, as these are the cells responsible for presenting antigen and initiating an antigen specific T cell response. Wang, Zhan, and co-workers6 describe nanoparticles that deliver CpG oligonucleotides−known adjuvants that bind the Toll-like 9 receptor (TLR9) to initiate a pro-inflammatory response−with a peptide antigen for ovalbumin as a model protein directly to DCs ex vivo, followed by systemic injection of the DCs into the host body in a mouse model. In this study, gold nanoparticles are used to conjugate either CpG or the antigen, with variation of particle size, surface functionality, and loading. After exposure of the DCs, they are tracked in the mouse following injection; their homing and infiltration into the lymph are studied using noninvasive imaging. It was found that DCs trafficked to the lymph node and activated CD8+ T cells. Furthermore, the gold nanoparticle system outperformed other known cytokine cocktails and delivery of free drug versions of the adjuvant molecules. Additional mechanisms of activation and mechanistic pathways were discussed in this paper, thus providing insight into nanoparticle formulations for immune cell activation. Certain therapies can also target T cells, which are the cells that are often engaged in fighting the invading pathogen or regulating the immune response. T cells are not as prone to uptake of nanoparticles in comparison to macrophages and DCs and, for that reason, are much more difficult to engage using nanoparticle strategies. Landfester and Steinbrink and coworkers7 describe the use of IL-2, a cytokine that binds to a range of different T cell types via the CD25 receptor, as a ligand attached to starch nanocapsules that can be designed to carry a range of cargoes. The nanocapsules were found to be taken up effectively by T cells via receptor mediated mechanisms and the dependence on ligand density in receptor clustering and cellular uptake, illustrating mechanisms to directly manipulate this important immune cell type.
known DNA sequence associated with a given pathogen; each DNA type is associated with a different QD color, which can be read on a chip by correlating the presence of bound DNA and microbead fluorescence. The sample used is DNA extracted from lysed cells and amplified using an isothermal amplification method. The resulting device can analyze these samples in a 20 to 60 min time period and can differentiate between several different blood-borne infectious diseases, including HIV, Hep B, and H1N1. The readout can be accomplished with a Smartphone camera, and the entire device is easily handheld and portable for use in a number of different settings in developing countries and remote settings. Monitoring of food and water for potential pathogens can be just as important as monitoring humans, in particular in avoiding some of the common sources of food-borne illnesses such as Salmonella, Listeria, and E. coli. For such applications, it is important to be able to detect very low levels of bacteria, ideally in a rapid and inexpensive fashion in order to have a viable and efficient means of testing water and food before use and for regular analysis. The work of Santra and co-workers4 applies magneto-fluorescence as a means of detection of E. coli in food and water systems. The authors combine two methods of detection−magnetic resonance and fluorescence−in a manner that allows coverage of a broad range of bacterial concentrations, from very low numbers (magnetic) to larger concentrations (fluorescence). Iron oxide nanoparticles with poly(acrylic acid) (PAA) bound to the surfaces are further modified with an antibody against the bacterial cell membrane and then bound to a fluorescent optical dye, DiI. The resulting 60 to 70 nm particles are then dosed to samples, and magnetic relaxation and fluorescence signals are used to determine bacteria concentrations reliably down to 1 CFU, while also remaining a quantitative measure at much higher levels, thus yielding a technology suitable for broad use in the field.
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VACCINES An area that is more emergent at the intersection of nanotechnology and infectious disease is the design and delivery of vaccines. There are a number of opportunities in this area, including the localized or systemic controlled release of vaccine components to the body and the manipulation of the immune response. Nanoparticles can play a role in the delivery of specific antigens in combination with the adjuvants or cytokines that are often necessary to sufficiently activate immune cells such as dendritic cells (DCs) and T cells that play the key roles in initiating the adaptive immune response. Significant amounts of new work and effort have been directed toward vaccines in nanomedicine recently, with much of it focused on immunotherapy for cancer treatments; however, a greater number of nanoscientists and engineers have begun examining the challenges involved in vaccine design for a range of infectious diseases. The introduction of new subunit protein vaccines and engineered antigens has provided new opportunities to design vaccine formulations that are much safer than the inactivated virus systems of past decades. Unfortunately, these subunit protein systems are not potent enough alone to elicit the desired immune response and require presentation in a nanoparticulate form and the coadministration of molecules that can act as adjuvants, often targeting specific receptor types. Some of the more interesting of such receptors include pattern recognition receptors such as Toll-like receptors and NOD-like receptors. An excellent review article by Caruso and coworkers5 provides added insight into these design principles
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TREATMENT Nanomaterials have been a focus in the area of drug delivery for the past couple of decades, with much of the materials design focused on targeted delivery to cancer. Much of what the nanomedicine community has learned in this area is relevant to the design of nanoscale carriers for in vivo delivery to infected regions and the successful targeting of infectious microbes such as bacteria at sites of infection. Nanoparticles that are exposed to blood and serum, particularly for systemic delivery, must avoid high serum protein binding and rapid clearance or loss of efficacy. They must also be adaptive to the environment in a manner that allows delivery or release of a given agent or direct engagement of bacteria or viruses to enact a killing or disabling action. Concepts such as stealth properties, environmentally responsive capabilities, and synergistic packaging of combination drugs are important in the world of infectious disease. Along with similarities, there are several unique differences and challenges. One challenge in bacterial infections is the generation of a biofilm; bacteria in well-established biofilms are difficult to reach, and their dormant state makes them less responsive to antibacterial agents. Because the biofilm that forms within infected organs is often the cause of damage and 555
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prepared to encapsulate a hydrophobic antibiotic, in this case triclosan, within the degradable core. The resulting mixed micellar structures exhibit a neutral charge at physiological pH and an outer stealth PEG layer that allows penetration into the biofilm; once micelles begin to penetrate deeper into the film, the shift in pH down to more acidic levels within the biofilm leads to protonation of the PBAE block, which becomes hydrophilic and strongly positively charged within the micellar corona. The enhanced charge targets uptake and breakdown of the carriers by bacteria and greatly enhances both further penetration and bactericidal activity of the drug. This elegant materials design was clearly demonstrated in penetration and efficacy studies in S. aureus biofilms. The use of novel inorganic nanomaterials has also provided unique tools for addressing bacterial infections. Chen and coworkers10 have demonstrated the use of gold nanocages to impart photothermal therapy as a means of targeted treatment. Although many papers have presented evidence of the efficacy of light-induced thermal treatment in addressing cancer, this paper forays into the potential of this approach for eradicating bacteria in sepsis or in biofilms. In this example, gold nanocages are surface modified with a polydopamine coating, and daptomycin, one of the most effective antibiotics against Gram-positive species such as S. aureus, is incorporated into the outer layer using noncovalent interactions with the polydopamine film. Finally, an antibody targeting S. aureus is attached to this outer layer to enhance accumulation in the biofilm and direct the therapeutics to the desired bacterial cells. Laser irradiation leads to highly localized increases in temperature due to the light absorption of the gold nanostructures at specific wavelengths; the result is hyperthermia induced cell death. The photothermal effect alone reduces bacterial counts significantly, but over time the bacteria can recover; however, the incorporation of daptomycin, which is freed upon laser heating through thermal expansion and swelling of the PDA outer layer, greatly enhances cell killing efficacy for extended time periods. Theranostics provide a means of imaging disease in conjunction with treating it and is based on the use of imaging agents combined with drug components; this capability enables image-guided drug delivery approaches to enhance and target treatment. It is possible to take this concept, developed in the context of cancer drug delivery, and generate systems that are responsive to the infected environment. By coating a silica nanoparticle with the poly(allyl amine hydrochloride) (PAH), a simple synthetic polyamine, Chen and co-workers11 illustrated that PAH would exchange from the silica to the membrane surface of S. aureus based on electrostatic interactions. This favorable transfer was used as the basis of a dual delivery and imaging mechanism. PAH was partially conjugated with the photosensitive and self-quenching dye, Cypate, and poly(acrylic acid) was partially conjugated with the antibiotic vancomycin, which also exhibits a preferential transfer from silica to the bacteria membrane. A polyelectrolyte bilayer is formed on the negatively charged silica surface between the PAH and PAA conjugates. When the nanoparticle nears the surface of a bacterial cell membrane, the polyelectrolyte bilayer dissociates and binds to the bacteria. This step has the dual effect of disaggregating the Cypate dye and inducing fluorescence upon bacteria contact, and releasing the Vancomycin to the bacteria. The bacteria can then be readily imaged using near-IR fluorescence (NIRF) imaging over a period of multiple days. When laser light is used to activate absorption of the dye, highly
morbidity in infectious disease, it is important to design systems that can penetrate this biofilm. Also, infectious disease can be treated with a number of known antibiotics as well as newly evolving inhibitors and other treatment molecules; unfortunately, resistance can build against many molecular therapeutics, especially those that act on a biochemical mechanism. For this reason, the goal for newly evolved treatments is to minimize overexposure of antibiotics over extended periods and achieve maximum effect with minimal doses. New materials design has also led to new, more physical means of disrupting bacterial cell membranes through the interaction of amphiphilic segments and positively charged components with the negatively charged bacterial cell membrane and peptidoglycan cell wall. This approach, which mimics naturally occurring antimicrobial peptides, has been found to be much less prone to the development of resistance. Several highly effective antimicrobial polymers have been developed that utilize these principles and show promise for future application. Wong and co-workers8 utilized simple design principles to combine aspects of targeted nanoparticle delivery and antimicrobial systems in a singular polymer that chain-folds into a unimicellar nanoparticle in aqueous conditions. Using controlled radical polymerization methods, this group generated a well-defined random acrylate/acrylamide copolymer with three key types of monomer repeats with side groups: a short PEG oligomer that acts to provide water solubility and steric stabilization, a primary amine with short alkyl spacer which would be protonated at biologic pH and provide charge interaction with the cell membrane, and a hydrophobic side group that lends an amphiphilic nature to the system to enable both chain folding into a micellar structure and chain penetration into bacteria cell membranes. These single chain molecules generate self-aggregates consisting of a single polymer chain when diluted in aqueous solution, yielding 1− 2 nm sized constructs with a steric PEG shell. When these micellar systems contact bacteria, previously shielded positively charged amines, in conjunction with the hydrophobic domains of the polymer chain, are thought to engage the cell membrane and induce physical disruption. By varying the amines and the choice of hydrophobic group, they were able to optimize a system that achieves 99.99% killing efficiency of Pseudomonas aeruginosa, effective against both forms in suspension and in an established biofilm. The nanoparticle construct exhibited a 1 to 2 log better therapeutic index−the ratio of hemocompatibility to minimum inhibitory concentration−to the current Gramnegative drug of last resort, colistin, indicating increased safety at micromolar concentrations of polymer, and it was found to exhibit low tendencies toward antimicrobial resistance. Dynamics within molecular constructs is indeed beneficial for design of nanomaterials that can be administered to the bloodstream or in the presence of serum or plasma while maintaining an ability to interact or engage microbes directly. Such dynamics may be achieved by rearrangements of micellar assemblies or by shifts in the degree and nature of ionization of nanostructures in response to the infected environment. Just as researchers have found it possible to target tumors via their microenvironment, it is possible to take advantage of the hypoxic nature of biofilms or the high level of proteases present in the biofilm environment. Shi and co-workers9 demonstrated that by combining block copolymers consisting of a degradable hydrophobic polyester, polycaprolactone (PCL) with PEO, and PCL with a degradable poly(beta-aminoester) block which has tertiary amines within the repeat unit. These micelles were 556
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efficacy of treatments against localized infections in skin, wounds, and implants and may play a role in prevention of infection as well.
effective photothermal ablation and bacteria cell death result. Notably, the approach also appears to be low in cellular toxicity and biologically safe; injected nanoparticles exhibited long plasma half-lives and high accumulation and specificity for target infected tissues postinjection in mice. Many of the aforementioned examples are potentially adoptive for systemic delivery; however, a number of technologies have been directed toward topical application and localized delivery of therapeutic molecules or exposure to microbicidal surfaces. Silver has long been used for its antibacterial activity, which relies on the presence of silver ions to impact membrane permeation, DNA damage, and the generation of reactive oxygen species in bacteria. Although there are several limiting aspects to the use of silver as the primary mode of treatment for infection, including cellular toxicity, silver can be coupled with highly effective antibiotics like daptomycin to increase killing efficiency by introducing additional modes of cell death. Xie and co-workers12 present the generation of hybrid therapeutic nanoparticles that combine these two effective antibiotic strategies in a manner that is synergistic, enabling multiple mechanisms to be engaged at once, thus making resistance less likely. Key to the approach is the use of Ag nanocrystals that are just a few nanometers in size and which can be engineered to precise numbers of atoms. These nanocrystal systems release silver ions in a more sustained fashion and enable larger amounts of silver to be active in the ionic state as well due to increased surface area. These sustained release nanocrystals were encapsulated in a daptomycin matrix cross-linked with the EDC coupling agent to yield an amide-linked matrix. It was hypothesized that the silver nanocrystal surfaces were decorated with lipophilic daptomycin, which is thought to exert lipophilic properties to penetrate cell membranes. The researchers reported evidence of a strong ROS response and significant DNA damage in these combination systems that enable improved therapeutic effect. A simple and fully biologically derived approach to topical systems includes the generation of silica nanoparticles as stabilizers for microcapsules for therapeutic capability. In the paper from Rotello and co-authors,13 bacterial biofilms are penetrated using a cinnamaldehyde and peppermint oil organic phase that is stabilized in the presence of silane modified silica nanoparticles bearing hydrophobic groups that stabilize the emulsion and result in fairly defined microsphere formulation. The silica can then be further modified if desired to optimize stabilization of the emulsion. The resulting systems provide a means of generating stable delivery systems for topical applications. Additional innovative approaches toward localized treatment include the incorporation of novel therapeutics such as molecular inhibitors within polymeric matrices. Lynn and coworkers14 incorporated a peptide that blocks quorum sensing between bacteria cells within the electrospun nanofibers of a polymeric coating that can be used to coat dressings and biomedical implants. The inhibitor blocks some of the virulence factors of infection and prevents colonization of bacteria in niche environments of the host and formation of a biofilm, thus greatly lowering the impact of the bacterial presence. In the PLGA degradable polymer nanofiber format, these molecules were released over a period of up to 3 weeks, providing a sustained period under which bacterial activity is significantly lowered, without impacting healthy mammalian cells. These kinds of approaches, alone or in conjunction with more traditional antibiotic treatments, may greatly improve the
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CONCLUSION Infectious diseases in all of its forms present important scientific and engineering problems that must be addressed to curtail the issues of resistant strains, lack of drug efficacy or drug sufficiency to address rising new modes of infection, and the challenges of addressing established infections, difficult to treat biofilms, sepsis, and other modes of pathogenic disease. Nanoscience provides many new and potentially exciting solutions to a number of these challenges, from detection of pathogens and monitoring of the immune state to novel modes of delivery and design of new macromolecular modes of killing or disabling pathogens. This direction is a new one for nanomedicine and nanotechnology, and there is a great deal left to learn about the mechanisms by which the disease can be addressed or ultimately prevented. As the field grows, we must introduce more of these fascinating new systems in vivo and work with biologists and clinicians to develop meaningful models to test both vaccines and treatments of infectious disease. There are opportunities in the design of more systems for systemic delivery of therapeutics using targeting approaches to address infected and inflamed organs, such as the lung or other niches. Nanomaterials are uniquely advantaged in accessing biofilms, and better understanding of the nature of nanomaterial penetration and dissemination in biofilms will greatly educate the field, as outlined in a recent Viewpoint in ACS Infectious Diseases.15 Vaccine systems will benefit from targeting of organs like the skin that contain high numbers of immune cells, and mechanistic studies are needed to further understand how to better design vaccine and adjuvant combinations. Sensing and detection systems will continue to improve, but improvements in ligand design, speed of processing, and rapid design for the recognition of new pathogens will speed progress in getting such systems to market and to developing countries. The field presents a frontier of new and compelling problems−now nanoscientists need only engage, bring their toolsets, and join the fight to address this important global health issue.
Paula T. Hammond
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Department of Chemical Engineering and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
AUTHOR INFORMATION
ORCID
Paula T. Hammond: 0000-0002-9835-192X Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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(1) Lee, J. R., Haddon, D. J., Gupta, N., Price, J. V., Credo, G. M., Diep, V. K., Kim, K., Hall, D. A., Baechler, E. C., Petri, M., Varma, M., Utz, P. J., and Wang, S. X. (2016) High-Resolution Analysis of Antibodies to Post-Translational Modifications Using Peptide Nanosensor Microarrays. ACS Nano 10 (12), 10652−10660. (2) Chen, P. Y., Chung, M. T., McHugh, W., Nidetz, R., Li, Y. W., Fu, J. P., Cornell, T. T., Shanley, T. P., and Kurabayashi, K. (2015)
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Multiplex Serum Cytokine Immunoassay Using Nanoplasmonic Biosensor Microarrays. ACS Nano 9 (4), 4173−4181. (3) Ming, K., Kim, J., Biondi, M. J., Syed, A., Chen, K., Lam, A., Ostrowski, M., Rebbapragada, A., Feld, J. J., and Chan, W. C. W. (2015) Integrated Quantum Dot Barcode Smartphone Optical Device for Wireless Multiplexed Diagnosis of Infected Patients. ACS Nano 9 (3), 3060−3074. (4) Banerjee, T., Sulthana, S., Shelby, T., Heckert, B., Jewell, J., Woody, K., Karimnia, V., McAfee, J., and Santra, S. (2016) Multiparametric magneto-fluorescent nanosensors for the ultrasensitive detection of Escherichia coli O157: H7. ACS Infect. Dis. 2 (10), 667−673. (5) Gause, K. T., Wheatley, A. K., Cui, J. W., Yan, Y., Kent, S. J., and Caruso, F. (2017) Immunological Principles Guiding the Rational Design of Particles for Vaccine Delivery. ACS Nano 11 (1), 54−68. (6) Zhou, Q. Q., Zhang, Y. L., Du, J., Li, Y., Zhou, Y., Fu, Q. X., Zhang, J. G., Wang, X. H., and Zhan, L. S. (2016) Different-Sized Gold Nanoparticle Activator/Antigen Increases Dendritic Cells Accumulation in Liver-Draining Lymph Nodes and CD8+T Cell Responses. ACS Nano 10 (2), 2678−2692. (7) Frick, S. U., Domogalla, M. P., Baier, G., Wurm, F. R., Mailander, V., Landfester, K., and Steinbrink, K. (2016) Interleukin-2 Functionalized Nanocapsules for T Cell-Based lmmunotherapy. ACS Nano 10 (10), 9216−9226. (8) Nguyen, T. K., Lam, S. J., Ho, K. K., Kumar, N., Qiao, G. G., Egan, S., Boyer, C., and Wong, E. H. (2017) Rational Design of SingleChain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria. ACS Infect. Dis. 3 (3), 237−248. (9) Liu, Y., Busscher, H. J., Zhao, B. R., Li, Y. F., Zhang, Z. K., van der Mei, H. C., Ren, Y. J., and Shi, L. Q. (2016) Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms. ACS Nano 10 (4), 4779−4789. (10) Meeker, D. G., Jenkins, S. V., Miller, E. K., Beenken, K. E., Loughran, A. J., Powless, A., Muldoon, T. J., Galanzha, E. I., Zharov, V. P., Smeltzer, M. S., and Chen, J. (2016) Synergistic photothermal and antibiotic killing of biofilm-associated Staphylococcus aureus using targeted antibiotic-loaded gold nanoconstructs. ACS Infect. Dis. 2 (4), 241−250. (11) Zhao, Z. W., Yan, R., Yi, X., Li, J. L., Rao, J. M., Guo, Z. Q., Yang, Y. M., Li, W. F., Li, Y. Q., and Chen, C. Y. (2017) BacteriaActivated Theranostic Nanoprobes against Methicillin-Resistant Staphylococcus aureus Infection. ACS Nano 11 (5), 4428−4438. (12) Zheng, K. Y., Setyawati, M. I., Lim, T. P., Leong, D. T., and Xie, J. P. (2016) Antimicrobial Cluster Bombs: Silver Nanoclusters Packed with Daptomycin. ACS Nano 10 (8), 7934−7942. (13) Duncan, B., Li, X. N., Landis, R. F., Kim, S. T., Gupta, A., Wang, L. S., Ramanathan, R., Tang, R., Boerth, J. A., and Rotello, V. M. (2015) Nanoparticle-Stabilized Capsules for the Treatment of Bacterial Biofilms. ACS Nano 9 (8), 7775−7782. (14) Kratochvil, M. J., Yang, T., Blackwell, H. E., and Lynn, D. M. (2017) Nonwoven Polymer Nanofiber Coatings That Inhibit Quorum Sensing in Staphylococcus aureus: Toward New Nonbactericidal Approaches to Infection Control. ACS Infect. Dis. 3 (4), 271−280. (15) Wang, L. S., Gupta, A., and Rotello, V. M. (2016) Nanomaterials for the treatment of bacterial biofilms. ACS Infect. Dis. 2 (1), 3−4.
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