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GIVING GUT BACTERIAL INFECTIONS THE GOLDEN TOUCH Infections in the gut caused by Escherichia coli can cause a host of serious problems, including peritonitis, cholecystitis, appendicitis, and even life-threatening septicemia, if the infection enters the bloodstream. Although antibiotics can effectively treat these infections, they can cause secondary issues, such as diarrhea, due to an imbalance between different types of intestinal microflora. Antibiotics kill both probiotic and pathogenic bacteria as well as intestinal epithelial cells, and this microflora imbalance has been linked to several chronic metabolic diseases, including diabetes, hypoglycemia, gout, and protein energy malnutrition. Seeking ways to fight gut bacterial infections while avoiding these problems, Li et al. (DOI: 10.1021/acsnano.9b01002) report that gold nanoparticles coated with an antibacterial agent can effectively fight gut E. coli infections in an animal model, while also promoting a healthy balance of intestinal microflora. The researchers developed nanoparticles coated with 4,6-diamino-2-pyrimidinethiol (DAPT) and then administered them to mice infected with E. coli. Unlike animals that received plain gold nanoparticles or the antibiotic levofloxacin, those that received the DAPT-coated nanoparticles completely cleared their infections and had significantly reduced inflammation and damage to the small intestines. In addition, these nanoparticles maintained a healthy balance and diversity of intestinal microflora, even after 28 days of oral administration. In contrast, the richness of microflora decreased after administration of uncoated gold nanoparticles or levofloxacin. The DAPT-coated nanoparticles also appeared to cause no significant toxicity, with the vast majority expelled through feces. The authors suggest that these qualities could make DAPT-coated nanoparticles a better alternative to antibiotics for gut bacterial infections.
through a nanosized pore or gap. One such strategy is quantum-tunneling-based DNA sequencing, which involves passing DNA through a nanosized gap between conductive materials, such as metal and graphene. Sequence information can be derived from tracing a tunnel current as the current intensity changes according to the molecular conductance of nucleotides passing close to a pair of electrodes. However, for this method to become viable, a major challenge must be resolved: The molecular conductance of DNA’s four nucleotides overlap significantly, with adenine and cytosine being so similar that they are essentially indistinguishable. To counter this issue, Furuhata et al. (DOI: 10.1021/ acsnano.9b01250) developed a chemical approach that replaces the canonical adenosine with a more highly conductive analog. Experiments that involved running a series of nucleotide analogs through a 0.6 nm gap between gold electrodes in a mechanically controlled break junction showed that their molecular conductance is highly correlated with the energy level of the highest occupied molecular orbital (HOMO). One of these nucleotides, 7-deaza dA (dzdA), showed significant promise in overcoming the overlap in conductance since its HOMO level was closer to the electrodes’ Fermi level. Further study showed that this analog could be recognized as the canonical adenosine by DNA polymerases enzymatically incorporated into DNA samples, significantly changing the conducted current measurement of strands that include it. The authors suggest that this approach holds promise toward making quantum-tunneling-based DNA sequencing a reality.
TARGETING RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) affects up to 1% of the world’s population, causing severe inflammation in joints and damage to bones and cartilage. To counter these issues, this disease is often treated with methotrexate, a folate analog that promotes an anti-inflammatory state. Although this drug can be effective even at low doses, long-term systemic administration often results in suboptimal response and off-target systemic toxicities, including impaired immunity that can lead to opportunistic infections. Being able to target and to deliver therapies directly to arthritic joints with high efficiency and specificity could help improve response while also decreasing undesirable side effects.
A MORE CONDUCIVE WAY TO SEQUENCE DNA Over the past several years, researchers have developed a variety of methods for electrically detecting DNA by passing it © 2019 American Chemical Society
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Published: May 28, 2019 4865
DOI: 10.1021/acsnano.9b03594 ACS Nano 2019, 13, 4865−4868
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Cite This: ACS Nano 2019, 13, 4865−4868
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Toward that end, Liu et al. (DOI: 10.1021/acsnano.9b01710) report a method to target methotrexate directly to the affected joint environment. Their method relies on the glycoprotein SPARC (secreted protein acidic and rich in cysteine), which is upregulated in atherosclerotic lesions and the microenvironment of various aggressive cancers. Hypothesizing that SPARC might also be overexpressed in inflamed joints, the researchers performed a series of experiments that tested this idea. They fabricated methotrexate into nanoparticles made of human serum albumin, a protein for which SPARC has a high affinity. Experiments in RA mouse models using these nanoparticles marked with fluorophores showed that they lingered in arthritic joints, successfully inhibiting inflammation, bone erosion, and cartilage damage, even at half the dosage of free methotrexate administered to other mice. Further investigation showed no signs of systemic toxicity. The authors suggest that these targeting nanoparticles offer a rational and innovative approach for RA with attractive potential for clinical translation.
Precoating had little effect on these properties. The authors suggest that this improved understanding of fouling and stealth could eventually help unlock the potential of particle-based medicines and vaccines.
DELVING DEEP INTO VELVET WORM SLIME Protein-based biopolymeric fibers, such as silk and mussel byssus, have spurred the design of polymeric materials with advanced properties, such as self-healing, wet adhesion, and exceptional toughness. One common key attribute to these materials is the ease and economy of processing as the fluid precursors transition into solids. Unlike many synthetic polymers, this natural process occurs under ambient conditions without the need for harsh solvents or high temperatures and without producing toxic byproducts. Velvet worms, terrestrial vertebrates that live on the forest floors of subtropical and equatorial regions, also produce a liquid biopolymer slime used for hunting that rapidly solidifies to form glassy polymer fibers with high stiffness, a process that can be reversed with hydration. However, the molecular mechanism underlying this behavior has not been elucidated. Previous work has shown the slime to be an emulsion of nanoscale charge-stabilized condensed droplets composed primarily of large phosphorylated proteins, which coalesce and self-organize into nano- and microfibrils that can be drawn into macroscopic fibers under mechanical shear. Baer et al. (DOI: 10.1021/acsnano.9b00857) built on this research using wide-angle X-ray diffraction and vibrational spectroscopy coupled with in situ shear deformation to examine this unusual material. In contrast to previous work that suggested that the main phosphorylated protein component was unstructured, Baer et al.’s findings show a significant β-crystalline structure in the storage phase. Shearing induces partial unfolding, a first step in the rapid self-organization of the nanofibrils into fibers. The authors suggest that these findings could help guide design principles for sustainable, reversible synthetic polymers of the future.
NO HARM, NO FOUL: BIOMOLECULAR CORONA AND CELLULAR ASSOCIATION A long circulation half-life is a key attribute for nanoparticle drug carriers. Hence, it is important to design these vehicles to avoid associations with immune cells. However, these carriers are exposed to a complex mix of proteins, sugars, and lipids that can form a biomolecular corona on their surfaces that affects cellular associations. To modulate this effect, researchers have developed “low-fouling” nanoparticles, which have low affinities for a wide variety of protein species and are commonly assumed to have reduced cellular interactions. However, it is unclear how particle design, biomolecular corona composition, and human immune cell interactions relate, preventing an accurate prediction of biological interactions for these materials. To investigate this question, Weiss et al. (DOI: 10.1021/ acsnano.9b00552) analyzed two different types of nanoparticles: high-fouling mesoporous silica particles and lowfouling zwitterionic poly(2-(methacryloyloxy)-ethyl phosphorylcholine) particles. The researchers tested each particle type’s interactions with blood components before and after precoating with serum albumin, immunoglobulin G, or complement protein C1q, characterizing both in terms of absolute formation of proteins using sodium dodecyl sulfate polyacrylamide gel electrophoresis and relative abundance of protein types using mass spectrometry and proteomics. Their results show that the low-fouling nanoparticles had reduced interactions with both serum proteins and cells compared to the high-fouling nanoparticles. In addition, enrichment for particular proteins correlated with specific cellular interactions. 4866
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DESIGNING A BETTER HIV VACCINE HIV continues to be a critical global health challenge, with nearly two million new infections around the world each year. For decades, researchers have strived to reduce its spread by developing an effective vaccine. However, this goal has been elusive. The most promising vaccine candidate thus far conferred a modest 30% protection against infection. To improve efficacy, it is critical to understand the factors that affect immune response, including the effective combination of antigen and adjuvant, as well as antigen−carrier interactions. Dacoba et al. (DOI: 10.1021/acsnano.8b07662) evaluated these vaccine characteristics, investigating the influence of polysaccharide-based nanoparticles and their bonds on a promising antigen and adjuvant. The researchers chose to use a protease cleavage site peptide, an antigen that is highly conserved across HIV1 strains, with polyinosinic:polycytidylic acid as the adjuvant. They conjugated the antigen to either of two different nanoparticles, chitosan or hyaluronic acid, through either a stable or cleavable bond. They then associated these constructs to an oppositely charged polymer, dextran sulfate or chitosan, along with the adjuvant. They compared these vaccines to nanoparticles associating the antigen by ionic interactions as controls. In mouse models, each of these nanosystems elicited a high antibody response against the antigen. However, combining the antigen with the adjuvant boosted activation of antigen presenting cells. In addition, T cell activation kinetics differed by vaccine formulation. The authors suggest that the nanoparticle composition and how the antigen is conjugated could play key roles in generating effective humoral and cellular responses for HIV vaccination.
themselves into different parts of the resulting supraparticle. The small particles were enriched at the surfaces of the supraparticles, assembled into close packed, crystalline regions with some line and dot defects. After cutting the particles in half and imaging through scanning electron microscopy, the researchers saw that the core of the supraparticles consisted mainly of the larger colloids, with the small ones filling the interstitial spaces. Simulations mirrored these results, underlining the robustness of the stratification process. When the researchers extended the drying time to 2 h by increasing the relative humidity, the large and small colloids became distributed more evenly in the resulting supraparticles. The authors suggest that these findings are relevant for applications in fabricating supraparticles for chromatography, catalysis, drug delivery, and photonics.
DESIGNING CUSTOM DNA ORIGAMI WITH SCAFFOLD SMITH For more than a decade, researchers have used DNA origami as a tool for basic science and applications in materials science, medicine, and other areas. This technique involves folding a long “scaffold” single strand of DNA into a user-defined shape, held together with a series of short “staple” DNA oligonucleotides. The scaffold sequence is usually taken as a fixed input from a library of generic sequences, typically based on the M13 phage genome, which is available to the community. However, because many properties of the resulting DNA origami result from the scaffold’s length and sequence, generic scaffold sequences may limit the scope of applications that can be addressed with this technique. To get around this restriction, Engelhardt et al. (DOI: 10.1021/acsnano.9b01025) developed a tool called “scaffold smith” that can construct design-specific scaffold sequences for DNA origami. Using this tool, the researchers made a variety of scaffold sequences, including mini scaffolds as short as 1024 bases and a set of fully orthogonal scaffolds for one-pot multiscaffold assembly of DNA origami made up of ∼38,000 base pairs. In addition, they created scaffolds containing functional motifs that enable DNAzyme-driven linearization and bisection of scaffolds or folded structures or a CpG-free scaffold with presumably lower immunogenicity for in vivo applications. Another customized scaffold included regular motifs that can be covalently cross-linked with UV pointwelding right after folding. The authors suggest that this tool can be used to design scaffolds with a host of other functional sequence motifs, including aptamers, recognition sites for DNA-binding proteins, and indicator sites for complementary DNA strands.
FOR BINARY COLLOIDAL DROPLETS, DRY, DRY AGAIN When a colloidal suspension evaporates, the previously dispersed colloids remain on the surface. When the suspension fully wets a surface, a film is formed. For partially wetting isolated droplets, particles aggregate into ring-like structures at low contact angles, whereas free droplets and droplets drying on superamphiphobic surfaces at high contact angles form radially symmetric spheres. In this latter scenario, the suspended colloids can coalesce into supraparticles. Previous research has shown that when these supraparticles are composed of differently sized particles, they tend to segregate within the resulting structure. However, this phenomenon has not been well understood. To investigate, Liu et al. (DOI: 10.1021/acsnano.9b00459) studied drying droplets of aqueous suspensions containing both small polystyrene colloids (338 nm) and larger ones (1430 nm). As these droplets dried on superamphiphobic surfaces, the suspended colloids coalesced and sorted 4867
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DYNAMIC TUNING OF LASING SPECTRA? NOT A STRETCH For nanoscale photonoic devices, such as light-active optical switches, light-emitting diodes, photodetectors, and waveguides, being able to tune the wavelength of coherent light dynamically will be critical to meet the demand for nanoscale light sources. Thus far, significant effort has concentrated on cavity-mode tuning, achieved through self-absorption, band gap engineering, electrical field modulation, and optical feedback of photonic crystals. However, each of these approaches has drawbacks that limit their use. Seeking a way to tune light dynamically, Ma et al. (DOI: 10.1021/acsnano.9b01735) looked to piezoelectric polarization of CdS. Using two different shapes of CdS nanobelts, parallelogram and ladder, the researchers attached both ends of the nanobelts to a poly(ethylene terephthalate) substrate. Tensile strain can be exerted on the CdS devices by applying bending strain to the substrate, enabling controllable straintuned modification of the resonant cavity mode from the spontaneous to the stimulated emission region. Here, experiments showed that the laser modulation was closely related to the [001] orientation of the nanobelts, with a red shift of the modes when strain is applied directly in the [001] orientation and a blue shift of half that value when strain is applied perpendicularly. This phenomenon suggests that piezoelectric polarization is the major regulating factor for changes in the refractive index. The authors note that these findings provide a concept for pressure nanosensing based on the shifts on the near-band-edge emission, Raman spectra, and lasing modes that occur with changing strain states.
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