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Melanosomes in nature have diverse morphologies, including spheres, rods, and platelets. By contrast, shapes of synthetic melanins have been almost entirely limited to spherical nanoparticles with few exceptions produced by complex templated synthetic methods. Here, we report a non-templated method to access synthetic melanins with a variety of architectures including spheres, sheets, and platelets. Three 1,8-dihydroxynaphthalene dimers (4-4', 2-4' and 2-2') were used as self-assembling synthons. These dimers pack to form well-defined structures of varying morphologies depending on the isomer. Specifically, distinctive ellipsoidal platelets can be obtained using 4-4' dimers. Solid-state polymerization of the preorganized dimers generates polymeric synthetic melanins while maintaining the initial particle morphologies. This work provides a new route to anisotropic synthetic melanins, where the building blocks are preorganized into specific shapes, followed by solid-state polymerization.

Melanin is a ubiquitous natural pigment found in a diverse array of organisms. Allomelanin is a class of nitrogen-free melanin often found in fungi. Herein, we find artificial allomelanin analogues exhibit high intrinsic microporosity and describe an approach for further increasing and tuning that porosity. Notably, the synthetic method involves an oxidative polymerization of 1,8-DHN in water, negating the need for multiple complex templating steps and avoiding expensive or complex chemical precursors. The well-defined morphologies of these nanomaterials were elucidated by a combination of electron microscopy and scattering methods, yielding to high-resolution 3D reconstruction based on small-angle X-ray scattering (SAXS) results. Synthetic allomelanin nanoparticles exhibit high BET areas, up to 860 m2/g, and are capable of ammonia capture up to 17.0 mmol/g at 1 bar. In addition, these nanomaterials can adsorb nerve agent simulants in solution and as a coating on fabrics with high breathability where they prevent breakthrough. We also confirmed that naturally derived fungal melanin can adsorb nerve gas simulants in solution efficiently despite lower porosity than synthetic analogues. Our approach inspires further analysis of yet to be discovered biological materials of this class where melanins with intrinsic microporosity may be linked to evolutionary advantages in relevant organisms and may in turn inspire the design of new high surface area materials.

Commonly known as a skin pigment, melanin has a vital role in UV radiation protection, primarily acting as a radical scavenger. However, a lesser known natural property of melanin, observed in some melanized organisms, is its capacity to adsorb toxins, including metals and organic molecules. Inspired by this, we set out to generate a synthetic porous melanin that would pave the way to enhancing the natural adsorbent properties of melanin and melanin-like materials. Here, we developed a method for the synthesis of porous polydopamine-based melanin utilizing a mesoporous silica (MS) nanoparticle template and characterized its physical properties. Through the oxidative polymerization of dopamine, followed by the etching of silica, we generated synthetic porous melanin (SPM) with the highest measured surface area of any known polydopamine-based material. The prepared SPM was effective for the uptake of various gases and organophosphate toxins, with the material exhibiting high selectivity for CO2 over CH4 and high potential for ammonia capture. Given the demonstrated advantages provided by synthetic porous melanin and melanin's role as an adsorbent in nature, we anticipate the discovery of porous analogues in biological systems.

In this work, we describe the radiolytic environment experienced by a polymer in water during liquid-cell transmission electron microscopy (LCTEM). We examined the radiolytic environment of aqueous solutions of poly(ethylene glycol) (PEG, 2400 g/mol) in the presence of sensitizing gold nanoparticles (GNPs, 100 nm) or radical scavenging isopropanol (IPA). To quantify polymer damage, we employed post-mortem analysis via matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS). This approach confirms IPA (1-10% w/v) can significantly mitigate radiolysis-induced damage to polymers in water, while GNPs significantly enhance damage. We couple LCTEM experiments with simulations to provide a generalizable strategy for assessing radiolysis mitigation or enhancement. This study highlights the caution required for LCTEM experiments on inorganic nanoparticles where solution phase properties of surrounding organic materials or the solvent itself are under investigation. Furthermore, we anticipate an increased use of scavengers for LCTEM studies of all kinds.

Melanin is a ubiquitous natural pigment that exhibits broadband absorption and high refractive index. Despite its widespread use in structural color production, how the absorbing material, melanin, affects the generated color is unknown. Using a combined molecular dynamics and finite-difference time-domain computational approach, this paper investigates structural color generation in one-component melanin nanoparticle-based supra-assemblies (called supraballs) as well as binary mixtures of melanin and silica (non-absorbing) nanoparticle-based supraballs. Experimentally produced one-component melanin and one-component silica supraballs, with thoroughly characterized primary particle characteristics using neutron scattering, produce reflectance profiles similar to the computational analogues, confirming that the computational approach correctly simulates both absorption and multiple scattering from the self-assembled nanoparticles. These combined approaches demonstrate that melanin's broadband absorption increases the primary reflectance peak wavelength, increases saturation, and decreases lightness factor. In addition, the dispersity of nanoparticle size more strongly influences the optical properties of supraballs than packing fraction, as evidenced by production of a larger range of colors when size dispersity is varied versus packing fraction. For binary melanin and silica supraballs, the chemistry-based stratification allows for more diverse color generation and finer saturation tuning than does the degree of mixing/demixing between the two chemistries., Comment: 40 pages, Figure 6

Nanoscale therapeutics have promise for the administration of therapeutic small molecules and biologics to the heart following myocardial infarction. Directed delivery to the infarcted region of the heart using minimally invasive routes is critical to this promise. In this review, we will discuss the advances and design considerations for two nanoscale therapeutics engineered to target the infarcted heart, nanoparticles and adeno-associated viruses.

Polymeric nanoscale materials able to target and accumulate in the tumor microenvironment (TME) offer promising routes for a safer delivery of anticancer drugs. By reaching their targets before significant amounts of drug are released, such materials can reduce off-target side effects and maximize drug concentration in the TME. However, poor drug loading capacity and inefficient nanomaterial penetration into the tumor can limit their therapeutic efficacy. Herein, we provide a novel approach to achieve high loading profiles while ensuring fast and efficient drug penetration in the tumor. This is achieved by co-polymerizing light-sensitive paclitaxel with monomers responsive to tumor-associated enzymes, and assembling the resulting di-block copolymers into spherical micelles. While light exposure enables paclitaxel to decouple from the polymeric backbone into light-activated micelles, enzymatic digestion in the TME initiates its burst release. Through a series of in vitro cytotoxicity assays, we demonstrate that these light-switch micelles hold greater potency than covalently linked, non-triggered micelles, and enable therapeutic profiles comparable to that of the free drug.

A major bottleneck in nanocarrier and macromolecule development for therapeutic delivery is our limited understanding of the processes involved in their uptake into target cells. This includes their active interactions with membrane transporters that co-ordinate cellular uptake and processing. Current strategies to elucidate the mechanism of uptake, such as painstaking manipulation of individual effectors with pharmacological inhibitors or specific genetic knockdowns, are limited in scope and biased towards previously studied pathways or the intuition of the investigators. Furthermore, each of these approaches present significant off-target effects, clouding the outcomes. We set out to develop and examine an unbiased whole-genome screening approach using pooled CRISPR/Cas9 libraries for its ability to provide a robust and rapid approach to identify novel effectors of material uptake. Enabling this, we developed a methodology termed fast-library of inserts (FLI)-seq for library preparation and quantitative readout of pooled screens that shows improved technical reproducibility and is easier to perform than existing methods. In this proof-of-concept study we use FLI-seq to identify a solute carrier protein family member, SLC18B1, as a transporter for polymeric micellar nanoparticles, confirming the viability for this approach to yield novel insights into uptake mechanisms.

The design and construction of crystalline protein arrays to selectively assemble ordered nanoscale materials has potential applications in sensing, catalysis and medicine. Whereas numerous designs have been implemented for the bottom-up construction of novel protein assemblies, the generation of artificial functional materials has been relatively unexplored. Enzyme-directed post-translational modifications are responsible for the functional diversity of the proteome and thus, could be harnessed to selectively modify artificial protein assemblies. In this study, we describe the use of phosphopantetheinyl transferases (PPTases), a class of enzymes that covalently modify proteins using coenzyme A (CoA), to site-selectively tailor the surface of designed, two-dimensional (2D) protein crystals. We demonstrate that a short peptide (ybbR) or a molecular tag (CoA) can be covalently tethered to 2D arrays to enable enzymatic functionalization using Sfp PPTase. The site-specific modification of two different protein array platforms is facilitated by PPTases to afford both small-molecule- and protein-functionalized surfaces with no loss in crystalline order. This work highlights the potential for chemoenzymatic modification of large protein surfaces towards the generation of sophisticated protein platforms reminiscent of the complex landscape of cell surfaces.

Solvated soft matter, both biological and synthetic, can now be imaged in liquids using liquid-cell transmission electron microscopy (LCTEM). However, such systems are usually composed solely of organic molecules (low

Herein we report photoinitiated polymerization-induced self-assembly (photo-PISA) of spherical micelles consisting of proapoptotic peptide-polymer amphiphiles. The one-pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150 mg/mL) with tunable peptide loadings up to 48 wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide-functionalized nanoparticles imbued the proapoptotic “KLA” peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1) proteolytic resistance compared to the oligopeptide alone; 2) significantly enhanced cell uptake permeability by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo-PISA in the large-scale synthesis of functional, proteolytically resistant peptide-polymer conjugates for intracellular delivery.

Dan Peer Laboratory of NanoMedicine, Dept. of Ce and Immunology, George S. Wise Facu Sciences, Dept. of Materials Science and E Faculty of Engineering and the Center for N and Nanotechnology, Tel Aviv University 69978, Israel. E-mail: Peer@tauex.tau.ac.il Department of Chemistry & Biochemistry, U California, San Diego, La Jolla, CA, 92093, U ngianneschi@ucsd.edu Dept. of Biological and Environmental E Cornell University, 226 Riley-Robb Hall, 14853, USA. E-mail: dl79@cornell.edu Cite this: DOI: 10.1039/c3tb90114a

Covalent organic frameworks (COFs) are highly modular porous crystalline polymers that are of interest for applications such as charge-storage devices, nanofiltration membranes, and optoelectronic devices. COFs are typically synthesized as microcrystalline powders, which limits their performance in these applications, and their limited solubility precludes large-scale processing into more useful morphologies and devices. We report a general, scalable method to exfoliate two-dimensional imine-linked COF powders by temporarily protonating their linkages. The resulting suspensions were cast into continuous crystalline COF films up to 10 cm in diameter, with thicknesses ranging from 50 nm to 20 μm depending on the suspension composition, concentration, and casting protocol. Furthermore, we demonstrate that the film fabrication process proceeds through a partial depolymerization/repolymerization mechanism, providing mechanically robust films that can be easily separated from their substrates.

In this Account, we describe the organization of functional peptides as densely arrayed side chains on polymer scaffolds which we introduce as a new class of material called poly(peptide). We describe two general classes of poly(peptide): (1) Peptide-Polymer Amphiphiles (PPAs), which consist of block copolymers with a dense grouping of peptides arrayed as the side chains of the hydrophilic block and connected to a hydrophobic block that drives micelle assembly, and (2) Protein-like Polymers (PLPs), wherein peptide-brush polymers are composed from monomers, each containing a peptide side chain. Peptides organized in this manner imbue polymers or polymeric nanoparticles with a range of functional qualities inherent to their specific sequence. Therefore, polymers or nanoparticles otherwise lacking bioactivity or responsiveness to stimuli, once linked to a peptide of choice, can now bind proteins, enter cells and tissues, have controlled and switchable biodistribution patterns, and be enzyme substrates (e.g., for kinases, phosphatases, proteases). Indeed, where peptide substrates are incorporated, kinetically or thermodynamically driven morphological transitions can be enzymatically induced in the polymeric material. Synergistically, the polymer enforces changes in peptide activity and function by virtue of packing and constraining the peptide. The scaffold can protect peptides from proteolysis, change the pharmacokinetic profile of an intravenously injected peptide, increase the cellular uptake of an otherwise cell impermeable therapeutic peptide, or change peptide substrate activity entirely. Moreover, in addition to the sequence-controlled peptides (generated by solid phase synthesis), the polymer can carry its own sequence-dependent information, especially through living polymerization strategies allowing well-defined blocks and terminal labels (e.g., dyes, contrast agents, charged moieties). Hence, the two elements, peptide and polymer, cooperate to yield materials with unique function and properties quite apart from each alone. Herein, we describe the development of synthetic strategies for accessing these classes of biomolecule polymer conjugates. We discuss the utility of poly(peptide)-based materials in a range of biomedical applications, including imaging of diseased tissues (myocardial infarction and cancer), delivering small molecule drugs to tumors with high specificity, imparting cell permeability to otherwise impermeable peptides, protecting bioactive peptides from proteolysis in harsh conditions (e.g., stomach acid and whole blood), and transporting proteins into traditionally difficult-to-transfect cell types, including stem cells. Poly(peptide) materials offer new properties to both the constituent peptides and to the polymers, which can be tuned by the design of the oligopeptide sequence, degree of polymerization, peptide arrangement on the polymer backbone, and polymer backbone chemistry. These properties establish this approach as valuable for the development of peptides as medicines and materials in a range of settings.

Melanin, with its high refractive index (RI) and broadband absorption, is an important biomaterial responsible for many of the vibrant structural colors observed in nature and for UV protection. Even though the RI plays an important role in the function of melanin, there is an ambiguity in its reported complex RI and a lack of understanding of whether and how the UV radiation, these materials are likely to experience under normal use, will affect the complex RI. Here, we measured the wavelength-dependent (360-1700nm) complex RI of synthetic melanin films before and after in situ UV treatment using ellipsometry. We modeled the ellipsometric data using a modified Tauc-Lorentz dispersion model and measured the thickness independently using atomic force microscopy. The UV radiation reduces the film thickness. Interestingly, we find that both the real and imaginary terms of the RI increase upon UV radiation. These experiments provide accurate measurements of the optical properties of melanin and a surprising result that synthetic melanin absorbs more light (similar to 25% increase in extinction coefficient) below 600nm after UV exposure.

The ability to optically monitor a chemical reaction and generate an in situ readout is an important enabling technology, with applications ranging from the monitoring of reactions in flow, to the critical assessment step for combinatorial screening, to mechanistic studies on single reactant and catalyst molecules. Ideally, such a method would be applicable to many polymers and not require only a specific monomer for readout. It should also be applicable if the reactions are carried out in microdroplet chemical reactors, which offer a route to massive scalability in combinatorial searches. We describe a convenient optical method for monitoring polymerization reactions, fluorescence polarization anisotropy monitoring, and show that it can be applied in a robotically generated microdroplet. Further, we compare our method to an established optical reaction monitoring scheme, the use of Aggregation-Induced Emission (AIE) dyes, and find the two monitoring schemes offer sensitivity to different temporal regimes of the polymerization, meaning that the combination of the two provides an increased temporal dynamic range. Anisotropy is sensitive at early times, suggesting it will be useful for detecting new polymerization “hits” in searches for new reactivity, while the AIE dye responds at longer times, suggesting it will be useful for detecting reactions capable of reaching higher molecular weights., Two complementary measurements, fluorescence polarization anisotropy and aggregation-induced emission, allow for in situ optical monitoring of polymerization reaction progress in droplets across varying temporal regimes of the reaction.

Melanin is a class of ubiquitous, heterogeneous, polymeric pigments. One of the most unusual features of melanin is the presence of stable persistent radicals, which has been reported to relate to ionizing radiation protection, including X-rays and gamma rays. In this work, we aimed to increase the radical content by introducing nitroxide radicals into synthetic melanin nanomaterials. Nanoparticles (NPs) were prepared by copolymerization of a stable radical modified monomer with the monomer dopamine. The radical content increased to 1 order of magnitude higher than that of the conventional melanin-like material, polydopamine. These radical NPs can enter human epidermal keratinocytes and form perinuclear caps, mimicking natural melanin synthesized by melanocytes. We demonstrated that these NPs display protective properties by scavenging reactive oxygen species, one of the most important biological effects of ionizing radiation exposure. This finding may have potential application for materials capable of mitigating side effects of clinical radiation therapy.

International audience; Cyclic (Alkyl)(Amino)Carbenes (CAACs) have become forceful ligands for gold due to their ability to form very strong ligandmetal bonds. Inspired by the success of Auranofin and other gold complexes as antitumor agents, we have studied the cytotoxicity of bis-and mono-CAAC-gold complexes on different cancer cell lines: HeLa (cervical cancer), A549 (lung cancer), HT1080 (fibrosarcoma) and Caov-3 (ovarian cancer). Further investigations aimed at elucidating their mechanism of action are described. This includes quantification of affinities for TrxR, evaluation of their bioavailability and determination of associated cell death process. Moreover, Transmission Electron Microscopy (TEM) was used to study morphological changes upon exposure. Noticeably, a significant reduction in non-specific binding to serum proteins was observed with CAAC complexes when compared to Auranofin. These results confirm the potential of CAAC-gold complexes in biological environments, which may result in more specific drug-target interactions and decreased side effects.

Polymerization reactions triggered by stimuli play a pivotal role in materials science, with applications ranging from lithography to biomedicine to adaptive materials. However, the development of chemically triggered, stimuli-responsive systems that can confer spatial and temporal control on polymerization remains a challenge. Herein, chemical-stimuli-induced polymerization based on a liquid crystal (LC) printhead is presented. The LC responds to a local chemical stimulus at its aqueous interface, resulting in the ejection of initiator into the solution to trigger polymerization. Various LC printhead geometries are designed, allowing programming of: i) bulk solution polymerization, ii) synthesis of a thin surface-confined polymeric coating, iii) polymerization-induced self-assembly of block copolymers to form various nanostructures (sphere, worm-like, and vesicles), and iv) 3D polymeric structures printed according to local solution conditions. The approach is demonstrated using amphiphiles, multivalent ions, and biomolecules as stimuli.

In nanomedicine, determining the spatial distribution of particles and drugs, together and apart, at high resolution within tissues, remains a major challenge because each must have a different label or detectable feature that can be observed with high sensitivity and resolution. We prepared nanoparticles capable of enzyme-directed assembly of particle therapeutics (EDAPT), containing an analogue of the Pt(II)-containing drug oxaliplatin, an 15N-labeled monomer in the hydrophobic block of the backbone of the polymer, the near-infrared dye Cy5.5, and a peptide that is a substrate for tumor metalloproteinases in the hydrophilic block. When these particles reach an environment rich in tumor associated proteases, the hydrophilic peptide substrate is cleaved, causing the particles to accumulate through a morphology transition, locking them in the tumor extracellular matrix. To evaluate the distribution of drug and EDAPT carrier in vivo, the localization of the isotopically labeled polymer backbone was compared to that of Pt by nanoscale secondary ion mass spectrometry (NanoSIMS). The correlation of NanoSIMS with super-resolution fluorescence microscopy revealed the release of the drug from the nanocarrier and colocalization with cellular DNA within tumor tissue. The results confirmed the dependence of particle accumulation and Pt(II) drug delivery on the presence of a Matrix Metalloproteinase (MMP) substrate and demonstrated antitumor activity. We conclude that these techniques are powerful for the elucidation of the localization of cargo and carrier, and enable a high-resolution assessment of their performance following in vivo delivery., Multiscale imaging methods to track drug-loaded nanoparticles are needed. Correlated optical and isotopic nanoscopy were used to study Pt(II)-loaded enzyme responsive micelle distribution in tissues.

Many natural silks produced by spiders and insects are unique materials in their exceptional toughness and tensile strength, while being lightweight and biodegradable–properties that are currently unparalleled in synthetic materials. Myriad approaches have been attempted to prepare artificial silks from recombinant spider silk spidroins but have each failed to achieve the advantageous properties of the natural material. This is because of an incomplete understanding of the in vivo spidroin-to-fiber spinning process and, particularly, because of a lack of knowledge of the true morphological nature of spidroin nanostructures in the precursor dope solution and the mechanisms by which these nanostructures transform into micrometer-scale silk fibers. Herein we determine the physical form of the natural spidroin precursor nanostructures stored within spider glands that seed the formation of their silks and reveal the fundamental structural transformations that occur during the initial stages of extrusion en route to fiber formation. Using a combination of solution phase diffusion NMR and cryogenic transmission electron microscopy (cryo-TEM), we reveal direct evidence that the concentrated spidroin proteins are stored in the silk glands of black widow spiders as complex, hierarchical nanoassemblies (∼300 nm diameter) that are composed of micellar subdomains, substructures that themselves are engaged in the initial nanoscale transformations that occur in response to shear. We find that the established micelle theory of silk fiber precursor storage is incomplete and that the first steps toward liquid crystalline organization during silk spinning involve the fibrillization of nanoscale hierarchical micelle subdomains.

Covalent organic frameworks writ large Covalent organic framework (COF) materials have been difficult to characterize structurally and to exploit because they tend to form powders or amorphous materials. Ma et al. studied a variety of three-dimensional COFs based on imine linkages (see the Perspective by Navarro). They found that the addition of aniline inhibited nucleation and allowed the growth of crystals large enough for single-crystal x-ray diffraction studies. Evans et al. describe a two-step process in which nanoscale seeds of boronate ester–linked two-dimensional COFs can be grown into micrometer-scale single crystals by using a solvent that suppresses the nucleation of additional nanoparticles. Transient absorption spectroscopy revealed superior charge transport in these crystallites compared with that observed in conventional powders. Science , this issue p. 48 , p. 52 ; see also p. 35

Author(s): Leriche, G; Manafirad, A; Nguyen, S; Bell, N; Patterson, JP; Thayumanavan, S; Yang, J; Dinsmore, AD; Gianneschi, NC | Abstract: Researchers report the synthesis of a new archaea-inspired tetraether lipid and study the mechanical elastic properties of membranes made from this bolalipid. To access structural diversity in the hydrophobic moiety of the lipids and to tune membrane properties, they have used used Huisgen 1,3-dipolar cycloaddition strategy to design and synthesize a tetraether lipid incorporating phytanyl side chains and polar 1,4 triazole rings known to change lipid packing. The researchers demonstrate the first example of the synthesis of phytanyl side chain incorporated tetraether lipids with 1,4-triazole rings. They also confirm the ability of lipids incorporating 1,4-triazole rings to form stable small and giant vesicles and examined their physical and mechanical properties using a micropipette aspiration technique.

Liquid crystals (LCs) offer the basis of stimuli-responsive materials that can amplify targeted molecular events into macroscopic outputs. However, general and versatile design principles are needed to realize the full potential of these materials. To this end, we report the synthesis of two homopolymers with mesogenic side chains that can be cleaved upon exposure to either H2 O2 (polymer P1) or UV light (polymer P2). Optical measurements reveal that the polymers dissolve in bulk LC and spontaneously assemble at nematic LC-aqueous interfaces to impose a perpendicular orientation on the LCs. Subsequent addition of H2 O2 to the aqueous phase or exposure of the LC to UV was shown to trigger a surface-driven ordering transition to a planar orientation and an accompanying macroscopic optical output. Differences in the dynamics of the response to each stimulus are consistent with sequential processing of P1 at the LC-aqueous interface (H2 O2 ) and simultaneous transformation of P2 within the LC (UV). The versatility of the approach is demonstrated by creating stimuli-responsive LCs as films or microdroplets, and by dissolving mixtures of P1 and P2 into LCs to create LC materials that respond to two stimuli. Overall, our results validate a simple and generalizable approach to the rational design of polymers that can be used to program stimuli-responsiveness into LC materials.

In this paper, we describe the use of liquid cell transmission electron microscopy (LCTEM) for inducing and imaging the formation of spherical micelles from amphiphilic block copolymers. Within the irradiated region of the liquid cell, diblock copolymers were produced which self-assembled, yielding a targeted spherical micellar phase via polymerization-induced self-assembly (PISA). Critically, we demonstrate that nanoparticle formation can be visualized in situ and that in the presence of excess monomer, nanoparticle growth occurs to yield sizes and morphologies consistent with standard PISA conditions. Experiments were enabled by employing automated LCTEM sample preparation and by analyzing LCTEM data with multi-object tracking algorithms designed for the detection of low-contrast materials., Understanding self-assembly is necessary for gaining synthetic control over assembled materials. We induced and observed the synthesis and simultaneous self-assembly of block copolymers in real time.

Decoration of cell membranes with biomolecules, targeting ligands and imaging agents is an emerging strategy to improve functionality of cell-based therapies. Compared to covalent (e.g., click) chemistry or genetic expression on the cell surface, lipid painting (i.e., incorporation of lipid-conjugated molecules into the cell bilayer) is a fast, non-damaging and less expensive approach. Previous studies demonstrated excellent incorporation and retention of distearyl indocarbocyanine dye DiI in membranes of cells in vitro and in vivo. In order to exploit the membrane stability of DiI, we synthesized an amino-DiI derivative, to which we subsequently conjugated an antibody (cetuximab), an enzyme (superoxide dismutase), and a small molecule (DyLight 800). Red blood cells have long been used as drug delivery vehicles so they were utilized as a model to study the incorporation of DiI conjugates in the plasma membrane. All the DiI constructs demonstrated fast and efficient ex vivo incorporation in the membrane of mouse RBCs, resulting in millions of exogenous molecules per RBC. Following an intravenous injection into mice, the molecules were detected on circulating RBCs for several days. DiI anchored molecules showed longer residence time in blood and significantly higher area under the curve (AUC) compared to free non-conjugated molecules. Thus, cetuximab, SOD and DyLight painted on RBC showed 5.5-fold, 6.5-fold and 78-fold increase in the AUC, respectively, compared to the non-modified molecules. Lipophilic indocarbocyanine anchors are a promising technology for incorporation of biomolecules and small molecules into biological membranes for in vivo applications.

Interfacial assemblies formed by polymeric amphiphiles at aqueous interfaces of thermotropic liquid crystals (LCs) can trigger multiscale changes in the organization of the LCs in response to recognition events. However, we have a limited understanding of the rules governing the rational design of LC-integrated polymeric amphiphiles. Herein, we report the synthesis of families of amphiphilic polymers that differ in (i) side-chain molecular structure, (ii) polymer architecture, and (iii) copolymer composition. We used this library in experiments to establish structure–property relationships relevant to the design of multifunctional polymers that can amplify and transduce biomolecular recognition events into optically detectable, macroscopic ordering transitions in LCs. We then utilized these structure–property relationships to guide the design of a peptide–polymer amphiphile (PPA) that assembles at the interface of LC droplets. Enzymatic cleavage of PPA-coated LC droplets by thermolysin directly triggered ...

Postsynthetic strategies for modifying metal-organic frameworks (MOFs) have proven to be an incredibly powerful approach for expanding the scope and functionality of these materials. Previously, we reported on the postsynthetic exchange (PSE) of metal ions and ligands in the University of Oslo (UiO) series of MOFs. Detailed characterization by several analytical methods, most notably inductively coupled plasma mass spectrometry (ICP-MS) and transmission electron microscopy (TEM) reveal that metal ion deposition on the surface of these MOFs occurs in the form of nanoscale metal oxides, rather than yielding exchanged metal sites within the MOFs, as was previously reported. By contrast, these combined analytical methods do confirm that ligand-based PSE can occur in these MOFs. These findings provide new insight into the postsynthetic manipulation of MOF materials, highlight the importance of rigorously characterizing these materials to correctly assign their composition and structure, and provide a new route to making hybrid solids with a MOF@metal oxide architecture.

The intracellular delivery of synthetic nucleic acids represents a major challenge in biotechnology and in biomedicine. Methods to deliver short, double-stranded RNA to living cells are of particular interest because of the potential to engage the RNA interference machinery and to regulate mRNA expression. In this work, we describe novel RNA-polymer amphiphiles that assemble into spherical micellar nanoparticles with diameters of ca. 15-30 nm and efficiently enter live cells without transfection reagents. Each micelle consists of approximately 100 RNA strands forming a densely packed corona around a polymeric core. Importantly, the surface-displayed RNA remains accessible for hybridization with complementary RNA. Chemical modification of the termini of hybridized RNA strands enabled the display of small organic moieties on the outer surface of the micelle corona. We found that some of these modifications can have a tremendous impact on cellular internalization efficiencies. The display of hydrophobic dabcyl or stilbene units dramatically increased cell uptake, whereas hydrophilic neutral hydroxy or anionic phosphate residues were ineffective. Interestingly, neither of these modifications mediated noticeable uptake of free RNA oligonucleotides. We infer that their high density display on micellar nanoparticle surfaces is key for the observed effect; achieved with local effective surface concentrations in the millimolar range. We speculate that weak interactions with cell surface receptors that are amplified by the multivalent presentation of such modifications may be responsible. The installation of small molecule ligands on nanomaterial surfaces via hybridization of chemically modified oligonucleotides offers a simple and straightforward way to modulate cellular uptake of nanoparticles. Biological functionality of micellar RNA was demonstrated through the sequence-specific regulation of mRNA expression in HeLa cells.

The development of degradable polymers has commanded significant attention over the past half century. Approaches have predominantly relied on ring-opening polymerization of cyclic esters (e.g., lactones, lactides) and N-carboxyanhydrides, as well as radical ring-opening polymerizations of cyclic ketene acetals. In recent years, there has been a significant effort applied to expand the family of degradable polymers accessible via olefin metathesis polymerization. Given the excellent functional group tolerance of olefin metathesis polymerization reactions generally, a broad range of conceivable degradable moieties can be incorporated into appropriate monomers and thus into polymer backbones. This approach has proven particularly versatile in synthesizing a broad spectrum of degradable polymers including poly(ester), poly(amino acid), poly(acetal), poly(carbonate), poly(phosphoester), poly(phosphoramidate), poly(enol ether), poly(azobenzene), poly(disulfide), poly(sulfonate ester), poly(silyl ether), and poly(oxazinone) among others. In this review, we will highlight the main olefin metathesis polymerization strategies that have been used to access degradable polymers, including (i) acyclic diene metathesis polymerization, (ii) entropy-driven and (iii) enthalpy-driven ring-opening metathesis polymerization, as well as (iv) cascade enyne metathesis polymerization. In addition, the livingness or control of polymerization reactions via different strategies are highlighted and compared. Potential applications, challenges and future perspectives of this new library of degradable polyolefins are discussed. It is clear from recent and accelerating developments in this field that olefin metathesis polymerization represents a powerful synthetic tool towards degradable polymers with novel structures and properties inaccessible by other polymerization approaches.

Seabirds have evolved numerous adaptations that allow them to thrive under hostile conditions. Many seabirds share similar colour patterns, often with dark wings, suggesting that their coloration might be adaptive. Interestingly, these darker wings become hotter when birds fly under high solar irradiance, and previous studies on aerofoils have provided evidence that aerofoil surface heating can affect the ratio between lift and drag, i.e. flight efficiency. However, whether this effect benefits birds remains unknown. Here, we first used phylogenetic analyses to show that strictly oceanic seabirds with a higher glide performance (optimized by reduced sink rates, i.e. the altitude lost over time) have evolved darker wings, potentially as an additional adaptation to improve flight. Using wind tunnel experiments, we then showed that radiative heating of bird wings indeed improves their flight efficiency. These results illustrate that seabirds may have evolved wing pigmentation in part through selection for flight performance under extreme ocean conditions. We suggest that other bird clades, particularly long-distance migrants, might also benefit from this effect and therefore might show similar evolutionary trajectories. These findings may also serve as a guide for bioinspired innovations in aerospace and aviation, especially in low-speed regimes. ispartof: JOURNAL OF THE ROYAL SOCIETY INTERFACE vol:18 issue:180 ispartof: location:England status: published

Recent advances in polymer chemistry, materials sciences, and biotechnology have allowed the preclinical development of sophisticated programmable nanomedicines and materials that are able to precisely respond to specific disease-associated triggers and microenvironments. These stimuli, endogenous to the targeted diseases, include pH, redox-state, small molecules and protein upregulation. Herein, we describe recent advances and innovative approaches in programmable soft materials capable of sensing the aforementioned disease associated stimuli and responding via a range of dynamic processes including morphological and size transitions, changes in mobility and retention, as well as disassembly. In this field generally, the majority of ongoing and past research effort has focused on oncology. Given this interest, we have chosen examples of the latest innovative approaches to chemo- and immunotherapy treatment strategies for cancer. Moreover, as the field broadens its attention, we highlight applications of programmable materials in other diseases, with a special focus on cardiovascular disease and diabetes mellitus, where limited attention has been paid by the field, but where many promising avenues exist with high potential impact.

Cellular uptake by macrophages and ensuing clearance by the mononuclear phagocyte system stands as a significant biological barrier for nanoparticle therapeutics. While there is a growing body of work investigating the design principles essential for imparting nanomaterials with long-circulating characteristics and macrophage evasion, there is still a widespread need for examining stimuli-responsive systems, particularly well-characterized soft materials, which differ in their physiochemical properties prior to and after an applied stimulus. In this work, we describe the synthesis and formulation of polymeric nanoparticles (NPs) and soluble homopolymers (Ps) encoded with multiple copies of a peptide substrate for proteases. We examined the macrophage cell uptake of these materials, which vary in their peptide charge and conjugation (via the N- or C-terminus). Following treatment with a model protease, thermolysin, the NPs and Ps undergo changes in their morphology and charge. After proteolysis, zwitterionic NPs showed significant cellular uptake, with the C-terminus NP displaying higher internalization than its N-terminus analogue. Enzyme-cleaved homopolymers generally avoided assembly and uptake, though at higher concentrations, enzyme-cleaved N-terminus homopolymers assembled into discrete cylindrical structures, whereas C-terminus homopolymers remained dispersed. Overall, these studies highlight that maintaining control over NP and polymer design parameters can lead to well-defined biological responses.

We report the preparation and study of Mn(III)-, Fe(III)-, Co(II)-, Ni(II)-, Cu(II)-, Zn(II)-, and Ga(III)-loaded polydopamine nanoparticles (PDA-NPs) via autoxidation polymerization of metal–dopamine complexes in the presence of free dopamine. An analysis of the doping range and parameters that influence final particle morphology is presented. In addition, magnetometry provides a probe of the general electronic structure and electronic interactions for Mn(III)-, Ni(II)-, and Co(II)-loaded PDA-NPs. PDA-NPs doped with Mn(III) are found to have high spin, low anisotropy, and weak magnetic coupling and are therefore predicted to have superior relaxivity behavior compared to previously studied Fe(III)-loaded PDA-NPs. Comparison of Mn(III)- and Fe(III)-loaded PDA-NP relaxivity confirms the predictive ability of the magnetometry measurements.

Metal-organic frameworks (MOFs) have emerged as a versatile platform for the rational design of multifunctional materials, combining large specific surface areas with flexible, periodic frameworks that can undergo reversible structural transitions, or "breathing", upon temperature and pressure changes, and through gas adsorption/desorption processes. Although MOF breathing can be inferred from the analysis of adsorption isotherms, direct observation of the structural transitions has been lacking, and the underlying processes of framework reorganization in individual MOF nanocrystals is largely unknown. In this study, we describe the characterization and elucidation of these processes through the combination of in situ environmental transmission electron microscopy (ETEM) and computer simulations. This combined approach enables the direct monitoring of the breathing behavior of individual MIL-53(Cr) nanocrystals upon reversible water adsorption and temperature changes. The ability to characterize structural changes in single nanocrystals and extract lattice level information through in silico correlation provides fundamental insights into the relationship between pore size/shape and host-guest interactions.

Herein we report a polymerization-induced self-assembly (PISA) process with ring-opening metathesis polymerization (ROMP). We utilize a peptide-based norbornenyl monomer as a hydrophobic unit to provide a range of nanostructures at room temperature yet at high solids concentrations of 20 wt % in combination with an oligoethylene glycol based norbornenyl monomer. Evaluation of the polymerizations under mild conditions highlight that good control is maintained along with high monomer conversion of greater than 99%, indicating that the living polymerization is unaffected during the PISA process. The demonstration broadens the scope of the PISA process to a new living polymerization methodology toward the development of easily accessible and highly functionalized nanostructures in situ.

A series of polymeric frameworks with functional assemblies were designed to alter the catalytic activity of covalently bound ReI electrocatalysts. Norbornenyl polymers containing positively charged quaternary ammonium salts, neutral phenyl, or negatively charged trifluoroborate groups were end-labelled with a ReI fac-tricarbonyl bipyridine electrocatalyst via cross metathesis. Electrochemical studies in acetonitrile under an inert atmosphere and with saturated CO2 indicate that the quaternary ammonium polymers exhibit a significantly lower potential for CO2 reduction to CO (ca. 300 mV), while neutral polymers behave consistently with what has been reported for the free, molecular catalyst. In contrast, the trifluoroborate polymers displayed a negative shift in potential and catalytic activity was not observed. It is demonstrated that a single catalytically active complex can be installed onto a charged polymeric framework, thereby achieving environmentally tuned reduction potentials for CO2 reduction. These materials may be useful as polymer-based precursors for preparing catalytic and highly ordered structures such as thin films, porous catalytic membranes, or catalytic nanoparticles.

A primary role of melanin in skin is the prevention of UV-induced nuclear DNA damage to human skin cells, where it serves to screen out harmful UV radiation. Melanin is delivered to keratinocytes in the skin after being excreted as melanosomes from melanocytes. Defects in melanin production in humans can cause diseases, many of which currently lack effective treatments due to their genetic origins (e.g., skin cancer, vitiligo, and albinism). The widespread prevalence of melanin-related diseases and an increasing interest in the performance of various polymeric materials related to melanin necessitates novel synthetic routes for preparing melanin-like materials. In this work, we prepared melanin-like nanoparticles (MelNPs) via spontaneous oxidation of dopamine, as biocompatible, synthetic analogues of naturally occurring melanosomes, and investigated their uptake, transport, distribution, and UV-protective capabilities in human keratinocytes. Critically, we demonstrate that MelNPs are endocytosed, undergo perinuclear aggregation, and form a supranuclear cap, or so-called microparasol in human epidermal keratinocytes (HEKa), mimicking the behavior of natural melananosomes in terms of cellular distribution and the fact that they serve to protect the cells from UV damage., In human skin, melanosomes form microscale umbrellas around nuclei of keratinocytes, shielding DNA from UV damage. Herein, entirely synthetic melanin nanoparticles are accepted by human keratinocytes and are used as artificial UV shields.

Covalent organic frameworks (COFs) are two- or three-dimensional (2D or 3D) polymer networks with designed topology and chemical functionality, permanent porosity, and high surface areas. These features are potentially useful for a broad range of applications, including catalysis, optoelectronics, and energy storage devices. But current COF syntheses offer poor control over the material’s morphology and final form, generally providing insoluble and unprocessable microcrystalline powder aggregates. COF polymerizations are often performed under conditions in which the monomers are only partially soluble in the reaction solvent, and this heterogeneity has hindered understanding of their polymerization or crystallization processes. Here we report homogeneous polymerization conditions for boronate ester-linked, 2D COFs that inhibit crystallite precipitation, resulting in stable colloidal suspensions of 2D COF nanoparticles. The hexagonal, layered structures of the colloids are confirmed by small-angle and wide-angle X-ray scattering, and kinetic characterization provides insight into the growth process. The colloid size is modulated by solvent conditions, and the technique is demonstrated for four 2D boronate ester-linked COFs. The diameter of individual COF nanoparticles in solution is monitored and quantified during COF growth and stabilization at elevated temperature using in situ variable-temperature liquid cell transmission electron microscopy imaging, a new characterization technique that complements conventional bulk scattering techniques. Solution casting of the colloids yields a free-standing transparent COF film with retained crystallinity and porosity, as well as preferential crystallite orientation. Collectively this structural control provides new opportunities for understanding COF formation and designing morphologies for device applications., Stable, colloidal covalent organic frameworks were synthesized, characterized by in situ techniques, and solution cast into free-standing, porous transparent films.

In this paper, we describe a method for the stabilization of low-boiling point (low-bp) perfluorocarbons (PFCs) at physiological temperatures by an amphiphilic triblock copolymer which can emulsify PFCs and be cross-linked. After UV-induced thiol-ene cross-linking, the core of the PFC emulsion remains in liquid form even at temperatures exceeding their boiling points. Critically, the formulation permits vaporization at rarefactional pressures relevant for clinical ultrasound.

Eumelanin is a ubiquitous natural pigment that has a broad absorption across ultraviolet (UV, 100-400 nm) and visible wavelengths (400-700 nm) and can protect against radiation. Synthetic eumelanin with properties similar to natural eumelanin has been made using dopamine or dihydroxyindole. Here, we use solid-state nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy to elucidate the chemical structure of synthetic eumelanins (made from dopamine and l-3,4-dihydroxyphenylalanine precursors) and investigate how their structures change after intensive UVA (315-400 nm) exposure. We first confirm that polydopamine has indole units. Upon UV exposure, the pyrrole ring in this indole unit remains intact, and a fraction of the six-membered benzyl ring is broken and the indole potentially converted to furo[3,4-b]pyrrole. This change in the chemical structure is accompanied by a release of carbon dioxide. In addition, the sepia (natural) eumelanin used for comparison is more stable than the synthetic eumelanin. Understanding the UVA degradation mechanism of eumelanin will help reveal the role of eumelanin in skin cancer and in the design of more efficient UV stabilizers.

We describe cyclic peptide progelators which cleave in response to UV light to generate linearized peptides which then self-assemble into gel networks. Cyclic peptide progelators were synthesized, where the peptides were sterically constrained, but upon UV irradiation, predictable cleavage products were generated. Amino acid sequences and formulation conditions were altered to tune the mechanical properties of the resulting gels. Characterization of the resulting morphologies and chemistry was achieved through liquid phase and standard TEM methods, combined with matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS).

Crystalline, electrically conductive, and intrinsically porous materials are rare. Layered 2D metal-organic frameworks (MOFs) break this trend. They are porous crystals that exhibit high electrical conductivity and are novel platforms for studying fundamentals of electricity and magnetism in two dimensions.1-8 Despite demonstrated applications,9-13 electrical transport in these remains poorly understood because of a lack of single crystal studies. Here, studies of single crystals of two 2D MOFs, Ni3(HITP)2 and Cu3(HHTP)2, uncover critical insights into their structure and transport. Conductivity measurements down to 0.3 K suggest metallicity for mesoscopic single crystals of Ni3(HITP)2, which contrasts with apparent activated conductivity for polycrystalline films. Microscopy studies further reveal that these MOFs are not isostructural as previously reported.14 Notably, single rods exhibit conductivities up to 150 S/cm, which persist even after prolonged exposure to the ambient. These single crystal studies confirm that 2D MOFs hold promise as molecularly tunable platforms for fundamental science and applications where porosity and conductivity are critical.

Contrast-enhanced ultrasound (CEUS) offers the exciting prospect of retaining the ease of ultrasound imaging while enhancing imaging clarity, diagnostic specificity, and theranostic capability. To advance the capabilities of CEUS, the synthesis and understanding of new ultrasound contrast agents (UCAs) is a necessity. Many UCAs are nano- or micro-scale materials composed of a perfluorocarbon (PFC) and stabilizer that synergistically induce an ultrasound response that is both information-rich and easily differentiated from natural tissue. In this work, we probe the extent to which CEUS is modulated through variation in a PFC stabilized with fluorine-modified polydopamine nanoparticles (PDA NPs). The high level of synthetic tunability in this system allows us to study signal as a function of particle aggregation and PFC volatility in a systematic manner. Separation of aggregated and non-aggregated nanoparticles lead to a fundamentally different signal response, and for this system, PFC volatility has little effect on CEUS intensity despite a range of over 50 °C in boiling point. To further explore the imaging tunability and multimodality, Fe(3+)-chelation was employed to generate an enhanced photoacoustic (PA) signal in addition to the US signal. In vitro and In vivo results demonstrate that PFC-loaded PDA NPs show stronger PA signal than the non-PFC ones, indicating that the PA signal can be used for in situ differentiation between PFC-loading levels. In sum, these data evince the rich role synthetic chemistry can play in guiding new directions of development for UCAs.

We describe the design, synthesis, and antitumor activity of an 18 carbon α,ω-dicarboxylic acid monoconjugated via an ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX (ODDA-PTX) prodrug readily forms a noncovalent complex with human serum albumin (HSA). Preservation of the terminal carboxylic acid moiety on ODDA-PTX enables binding to HSA in the same manner as native long-chain fatty acids (LCFAs), within hydrophobic pockets, maintaining favorable electrostatic contacts between the ω-carboxylate of ODDA-PTX and positively charged amino acid residues of the protein. This carrier strategy for small molecule drugs is based on naturally evolved interactions between LCFAs and HSA, demonstrated here for PTX. ODDA-PTX shows differentiated pharmacokinetics, higher maximum tolerated doses and increased efficacy in vivo in multiple subcutaneous murine xenograft models of human cancer, as compared to two FDA-approved clinical formulations, Cremophor EL-formulated paclitaxel (crPTX) and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).

Metal–organic nanotubes (MONTs) are tunable porous 1D materials that are envisioned to be complementary to carbon nanotubes for anisotropic applications. To date, characterization of MONTs relies on single crystal X-ray diffraction (SCXRD) to determine structure and composition. This requires crystals on the micrometer regime, effectively rendering bulk 3D materials. By tracking the growth of a MONT as a function of time with liquid-cell transmission electron microscopy (LCTEM), TEM, and SCXRD, it was possible to ascertain that the material in the bulk phase matches the nanomaterial in terms of molecular structure. This result allowed for the first measurements of finite bundles of MONTs on the nanometer scale. By employing in situ LCTEM, a time course of the formation of small bundles of MONTs could be acquired which provided mechanistic information on MONT formation which is of utility in reaction optimization and applications development.

The construction of hierarchical nanostructures with precise morphological and dimensional control has been one of the ultimate goals of contemporary materials science and chemistry, and the emulation of tailor-made nanoscale superstructures realized in the nature, using artificial building blocks, poses outstanding challenges. Herein we report a one-pot strategy to precisely synthesize hierarchical nanostructures through an in-situ initiation-growth process from a liquid crystalline block copolymer. The assembly process, analogous to living chain polymerization, can be triggered by small-molecule, macromolecule or even nanoobject initiators to produce various hierarchical superstructures with highly uniform morphologies and finely tunable dimensions. Because of the high degree of controllability and predictability, this assembly strategy opens the avenue to the design and construction of hierarchical structures with broad utility and accessibility., Construction of hierarchical nanostructures is important in material science, but precise morphological control remains a challenge. Here, the authors report a one-pot in-situ initiation-growth process from a liquid crystalline block copolymer to precisely control the morphology and dimensions of hierarchical nanostructures.