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A robust route to synthetic pheomelanin gives insight into the electronic, molecular and supramolecular structure of the natural product, further advancing our understanding of this important subfamily of melanin.

The first multivariate ligand MONTs were prepared and characterized and showed statistical copolymerization.

Decellularized extracellular matrix in the form of patches and locally injected hydrogels has long been used as therapies in animal models of disease. Here we report the safety and feasibility of an intravascularly infused extracellular matrix as a biomaterial for the repair of tissue in animal models of acute myocardial infarction, traumatic brain injury and pulmonary arterial hypertension. The biomaterial consists of decellularized, enzymatically digested and fractionated ventricular myocardium, localizes to injured tissues by binding to leaky microvasculature, and is largely degraded in about 3 d. In rats and pigs with induced acute myocardial infarction followed by intracoronary infusion of the biomaterial, we observed substantially reduced left ventricular volumes and improved wall-motion scores, as well as differential expression of genes associated with tissue repair and inflammation. Delivering pro-healing extracellular matrix by intravascular infusion post injury may provide translational advantages for the healing of inflamed tissues 'from the inside out'.

Two-dimensional (2D) covalent organic frameworks (COFs) are composed of structurally precise, permanently porous, layered macromolecular sheets, which are traditionally synthesized as polycrystalline solids with crystalline domain lengths smaller than 100 nm. Here, we polymerize imine-linked 2D COFs as suspensions of faceted single crystals in as little as 5 min at moderate temperature and ambient pressure. Single crystals of two imine-linked 2D COFs were prepared, consisting of a rhombic 2D COF (

Inspired by structural colors in avian species, various synthetic strategies have been developed to produce non-iridescent, saturated colors using nanoparticle assemblies. Mixtures of nanoparticles varying in particle chemistry (or complex refractive indices) and particle size have additional emergent properties that impact the color produced. For such complex multi-component systems, an understanding of assembled structure along with a robust optical modeling tool can empower scientists to perform intensive structure-color relationship studies and fabricate designer materials with tailored color. Here, we demonstrate how we can reconstruct the assembled structure from small-angle scattering measurements using the computational reverse-engineering analysis for scattering experiments (CREASE) method and then use the reconstructed structure in finite-difference time-domain (FDTD) calculations to predict color. We successfully, quantitatively predict experimentally observed color in mixtures containing strongly absorbing melanin nanoparticles and demonstrate the influence of a single layer of segregated nanoparticles on color produced. The versatile computational approach presented in this work is useful for engineering synthetic materials with desired colors without laborious trial and error experiments., 23 Pages, 5 Figures, 1 ToC Figure

Metal-organic frameworks (MOFs) constructed from Zr

Polyoxometalates (POMs) are versatile materials for chemical catalysis due to their tunable acidity and rich redox properties. While POMs have attracted significant attention in homogeneous catalysis, challenges regarding aggregation and instability in solvents often prevent the wide implementation of POMs as heterogeneous catalysts. Therefore, the successful incorporation of a POM into a solid support, such as a polymer, is desirable for practical applications where unique functionalities of the POM combine with the advantages of the polymer. In this work, we showcase how polymers of intrinsic microporosity (PIMs) can serve as matrices for anchoring a pure inorganic Keggin-type POM (H

Herein, we present the direct observation and quantification of a water-in-oil (w/o) emulsion, its destabilization, and the effect of additives on such processes at the nanoscale. This is achieved via liquid phase transmission electron microscopy (LPTEM), wherein a small volume of emulsion is encapsulated against vacuum in its liquid state to allow observation of its initial morphology and its evolution over time at excellent spatial and temporal resolution. Emulsions of this class are useful for delivering payloads of materials insoluble in their delivery medium and are currently widely used across food science, pharmaceuticals, and environmental applications. However, their utility is inherently limited by their thermodynamic tendency to demulsify, eventually leading to bulk phase separation. This occurs via several degradation mechanisms, operating at times collectively, and which are difficult to differentiate via traditional ensemble methods (e.g., light scattering), obscuring mechanistic nuances. LPTEM as a characterization technique has the potential to augment our understanding of emulsion behavior and improve performance and formulations. In this work, we also emphasize the importance of the included videographic Supporting Information data in demonstrating the behavior of the studied materials.

Biomacromolecules 24(1), 98 – 108 (2023). doi:10.1021/acs.biomac.2c00866, Intrinsically disordered peptide amphiphiles (IDPAs) present a novel class of synthetic conjugates that consist of short hydrophilic polypeptides anchored to hydrocarbon chains. These hybrid polymer-lipid block constructs spontaneously self-assemble into dispersed nanoscopic aggregates or ordered mesophases in aqueous solution due to hydrophobic interactions. Yet, the possible sequence variations and their influence on the self-assembly structures are vast and have hardly been explored. Here, we measure the nanoscopic self-assembled structures of four IDPA systems that differ by their amino acid sequence. We show that permutations in the charge pattern along the sequence remarkably alter the headgroup conformation and consequently alter the pH-triggered phase transitions between spherical, cylindrical micelles and hexagonal condensed phases. We demonstrate that even a single amino acid mutation is sufficient to tune structural transitions in the condensed IDPA mesophases, while peptide conformations remain unfolded and disordered. Furthermore, alteration of the peptide sequence can render IDPAs to become susceptible to enzymatic cleavage and induce enzymatically activated phase transitions. These results hold great potential for embedding multiple functionalities into lipid nanoparticle delivery systems by incorporating IDPAs with the desired properties., Published by American Chemical Soc., Columbus, Ohio

Peptide-brush polymers (PBPs), wherein every side-chain of the polymers is peptidic, represent a new class of proteomimetic with unusually high proteolytic resistance while maintaining bioactivity. Here, we sought to determine the origin of this behavior and to assess its generality via a combined theory and experimental approach. A series of PBPs with various polymer backbone structures were prepared and examined for their proteolytic stability and bioactivity. We discovered that an increase in the hydrophobicity of the polymer backbones is predictive of an elevation in proteolytic stability of the side-chain peptides. Computer simulations, together with small-angle X-ray scattering (SAXS) analysis, revealed globular morphologies for these polymers, in which pendant peptides condense around hydrophobic synthetic polymer backbones driven by the hydrophobic effect. As the hydrophobicity of the polymer backbones increases, the extent of solvent exposure of peptide cleavage sites decreases, reducing their accessibility to proteolytic enzymes. This study provides insight into the important factors driving PBP aqueous-phase structures to behave as globular, synthetic polymer-based proteomimetics., This study sheds light on the origin of peptide-brush polymers as globular proteomimetics and protein-like polymers by examining them for their structure and stability.

In this paper, we report the in situ growth of FF nanotubes examined via liquid-cell transmission electron microscopy (LCTEM). This direct, high spatial, and temporal resolution imaging approach allowed us to observe the growth of peptide-based nanofibrillar structures through directional elongation. Furthermore, the radial growth profile of FF nanotubes through the addition of monomers perpendicular to the tube axis has been observed in real-time with sufficient resolution to directly observe the increase in diameter. Our study demonstrates that the kinetics, dynamics, structure formation, and assembly mechanism of these supramolecular assemblies can be directly monitored using LCTEM. The performance of the peptides and the assemblies they form can be verified and evaluated using post-mortem techniques including time-of-flight secondary ion mass spectrometry (ToF-SIMS).

Nanoparticles that undergo a localized morphology change to target areas of inflammation have been previously developed but are limited by their lack of biodegradability. In this paper, we describe a low ring strain cyclic olefin monomer, 1,3-dimethyl-2-phenoxy-1,3,4,7-tetrahydro-1,3,2-diazaphosphepine 2-oxide (MePTDO), that rapidly polymerizes via ring-opening metathesis polymerization (ROMP) at room temperature to generate well-defined degradable polyphosphoramidates with high monomer conversion (>84%). Efficient MePTDO copolymerizations with norbornene-based monomers are demonstrated, including a norbornenyl monomer functionalized with a peptide substrate for inflammation-associated matrix metalloproteinases (MMPs). The resulting amphiphilic peptide brush copolymers self-assembled in aqueous solution to generate micellar nanoparticles (30 nm in diameter) which exhibit excellent cyto- and hemocompatibility and undergo MMP-induced assembly into micron scale aggregates. As MMPs are upregulated in the heart post-myocardial infarction (MI), the MMP-responsive micelles were applied to target and accumulate in the infarcted heart following intravenous administration in a rat model of MI. These particles displayed a distinct biodistribution and clearance pattern in comparison to non-degradable analogues. Specifically, accumulation at the site of MI, competed with elimination predominantly through the kidney rather than the liver. Together, these results suggest this as a promising new biodegradable platform for inflammation targeted delivery.

Allomelanin is a class of nitrogen-free melanin mostly found in fungi and, like all naturally occurring melanins, is hydrophilic. Herein, we develop a facile method to modify synthetic hydrophilic allomelanin to yield hydrophobic derivatives through post-synthetic modifications. Amine-functionalized molecules of various kinds can be conjugated to allomelanin nanoparticles under mild conditions with high loading efficiencies. Hydrophobicity is conferred by introducing amine-terminated alkyl groups with different chain lengths. We demonstrate that the resulting hydrophobic allomelanin nanoparticles undergo air/water interfacial self-assembly in a controlled fashion, which enables the generation of large-scale and uniform structural colors. This work provides an efficient and tunable surface chemistry modification strategy to broaden the scope of synthetic melanin structure and function beyond the known diversity found in nature.

Here we report the use of defects in ordered solvents to form, manipulate, and characterize individual molecular assemblies of either small-molecule amphiphiles or polymers. The approach exploits nanoscopic control of the structure of nematic solvents (achieved by the introduction of topological defects) to trigger the formation of molecular assemblies and the subsequent manipulation of defects using electric fields. We show that molecular assemblies formed in solvent defects slow defect motion in the presence of an electric field and that time-of-flight measurements correlate with assembly size, suggesting methods for the characterization of single assemblies of molecules. Solvent defects are also used to transport single assemblies of molecules between solvent locations that differ in composition, enabling the assembly and disassembly of molecular "nanocontainers". Overall, our results provide new methods for studying molecular self-assembly at the single-assembly level and new principles for integrated nanoscale chemical systems that use solvent defects to transport and position molecular cargo.

We report a novel glycan array architecture that binds the mannose-specific glycan binding protein, concanavalin A (ConA), with sub-femtomolar avidity. A new radical photopolymerization developed specifically for this application combines the grafted-from thiol-(meth)acrylate polymerization with thiol-ene chemistry to graft glycans to the growing polymer brushes. The propagation of the brushes was studied by carrying out this grafted-to/grafted-from radical photopolymerization (GTGFRP) at >400 different conditions using hypersurface photolithography, a printing strategy that substantially accelerates reaction discovery and optimization on surfaces. The effect of brush height and the grafting density of mannosides on the binding of ConA to the brushes was studied systematically, and we found that multivalent and cooperative binding account for the unprecedented sensitivity of the GTGFRP brushes. This study further demonstrates the ease with which new chemistry can be tailored for an application as a result of the advantages of hypersurface photolithography.

Summary The search for novel forms of computing to the dominant von Neumann model-based approach is important as it will enable different classes of problems to be solved. Molecular computers are a promising alternative to semiconductor-based computers given their potential biocompatibility and cost advantages. The vast space of chemical reactions makes molecules a tunable, scalable, and energy-efficient computational vehicle. In molecular computers, memory and processing units can be combined into a single, inherently parallelized device. Here, we present a microdroplet array molecular computer to solve combinatorial optimization problems by employing an Ising Hamiltonian to map problems heuristically to droplet-droplet interactions. The droplets represent binary digits and problems are encoded in intra- and inter-droplet reactions. We propose two implementations: first, a hybrid classical-molecular computer that enforces inter-droplet constraints in a classical computer and, second, a purely molecular computer where the problem is entirely pre-programmed in the nearest-neighbor droplet reactions.

High catalytic activity and substrate specificity make enzymes a rich source of inspiration for catalyst development. Co-opting the advantages of natural materials while tuning them to a modified f...

Background: The proto-oncogene Myc is known to play critical roles in tumorigenesis, being dysregulated in >70% of human cancers. Development of small molecule Myc drugs has been hampered due to the lack of suitable binding pockets. Myc inhibitory peptides H1, derived from the bHLH-LZ region, have been explored to address this. However, poor pharmacokinetic profiles have precluded clinical translation. Here, we use a novel modular platform technology referred to as the HYDRAC for the development of dual-functional Myc inhibitors/degraders. Methods: HYDRACs were generated using ROMP resulting in dense brush polymers where peptides occupy every side chain. Heterofunctional constructs were designed incorporating synergistic secondary sequences in addition to Myc-targeting H1. Specifically, a RRRG degron sequence was added to engage endogenous cellular machinery for targeted Myc degradation. Immunofluorescence and confocal microscopy were used to assess cellular penetration; cellular viability assays coupled with both cellular (isogenic pairs, Myc-dependent and independent lines) and biochemical (scrambled H1, monomeric peptides, etc) controls were used to assess anti-proliferative and Myc-specific responses. Myc engagement was assessed via biophysical assays and protein degradation monitored by Western blot. A CRISPR E3 ligase knockdown library and mass spec was used to identify pathways responsible for HYDRAC-induced protein degradation. Results: A library of HYDRACs with low PDI and predetermined DPs were generated. These compounds were shown to be cell-penetrating with antiproliferative effects at sub-micromolar IC50 values in a formulation- and Myc-dependent manner. HYDRAC treatment resulted in significant decreases in Myc protein levels, rescued by proteasomal inhibition with MG132. RNAseq showed selective overexpression of Myc pathway genes. Biophysical analysis showed strong HYDRAC-Myc interactions, in addtion to Myc protein present following pull-down of biotin-terminated HYDRACs. Selectivity studies revealed that HYDRAC activity requires an intact H1 targeting sequence. Identification of E3 ligases implicated in the degradation pathway are ongoing. Mice bearing transplanted Myc-CaP tumors showed delayed tumor growth following IP administration of Myc-degrading HYDRACs, with studies exploring the biodistribution and pharmacokinetic profile of the compound ongoing. Conclusion: We present a novel platform technology that addresses the challenges inherent to peptide delivery approaches. The presented work demonstrates the feasibility of HYDRACs for targeted Myc inhibition and degradation. This first-in-class compound also opens the door for the development of HYDRACs targeting other proteins of interest and multiplexing different E3 ligase recruiters for tissue or disease-specific activity. Citation Format: Max M. Wang, Mihai I. Truica, Brayley Gattis, Xiaoyu Zhang, Sarki Abdulkadir, Nathan C. Gianneschi. Inhibiting Myc using heterofunctional polymeric degrading chimeras (HYDRACs): a novel class of compounds capable of targeted protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2714.

Background: Patient-specific cancer vaccines derived from tumor antigen have been a promising therapeutic strategy, however, challenges remain in delivering vaccine components in a coordinated fashion to elicit antitumor responses. To overcome these, we developed rationally designed cancer vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics allowing for sustained targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing peptide antigens were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of PLPs with different sidechain linkage chemistries, degrees of polymerization (DP), and inclusion/exclusion of OEG were made. Cell uptake and functional assays using payload-specific T Cells were conducted to show antigen-specific responses. Ability of PLPs to co-deliver adjuvants in vivo was tested by electrostatically coupling 2’3’ cGAMP, forming stable nanostructures. Results: Conjugating peptide antigens to the PLP backbone using a cleavable disulfide linkage, which reduces intracellularly in APCs, resulted in increased endosomal localization, higher levels of induced T cell proliferation, cytokine production, and expression of activation markers in CTLs and APCs. Incorporating a diluent amount of OEG side chains reduced enzymatic degradation while increasing immunogenicity and APC uptake. Additionally, increasing the DP, and therefore the density of antigen side chains, further improved vaccine efficacy and resistance to proteolysis. Antigen-PLP conjugates enhanced dendritic cell activation and T-cell response only when paired with cells from their cognate system, with no activity in immune cells not expressing receptors for the payload, demonstrating antigen-specificity. Mice bearing established B16F10 tumors treated with gp100-PLPs showed significant increases in survival time and reduced tumor burden with corresponding changes in immune cell profiles. Impressively, mice treated with STING-PLP complexes had significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p Conclusion: This work validates the ability of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling, highlighting its potential to revolutionize cancer vaccinology. Citation Format: Max M. Wang, Mi Ran Choi, Brayley Gattis, Bin Zhang, Nathan C. Gianneschi. The protein-like polymer (PLP): A tunable proteomimetic nanoplatform for the development of rationally designed cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 813.

Melanin is ubiquitous in living organisms across different biological kingdoms of life, making it an important, natural biomaterial. Its presence in nature from microorganisms to higher animals and plants is attributed to the many functions of melanin, including pigmentation, radical scavenging, radiation protection, and thermal regulation. Generally, melanin is classified into five types-eumelanin, pheomelanin, neuromelanin, allomelanin, and pyomelanin-based on the various chemical precursors used in their biosynthesis. Despite its long history of study, the exact chemical makeup of melanin remains unclear, and it moreover has an inherent diversity and complexity of chemical structure, likely including many functions and properties that remain to be identified. Synthetic mimics have begun to play a broader role in unraveling structure and function relationships of natural melanins. In the past decade, polydopamine, which has served as the conventional form of synthetic eumelanin, has dominated the literature on melanin-based materials, while the synthetic analogues of other melanins have received far less attention. In this perspective, we will discuss the synthesis of melanin materials with a special focus beyond polydopamine. We will emphasize efforts to elucidate biosynthetic pathways and structural characterization approaches that can be harnessed to interrogate specific structure-function relationships, including electron paramagnetic resonance (EPR) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. We believe that this timely Perspective will introduce this class of biopolymer to the broader chemistry community, where we hope to stimulate new opportunities in novel, melanin-based poly-functional synthetic materials.

To improve their synthesis and ultimately realize the technical promise of two-dimensional covalent organic frameworks (2D COFs), it is imperative that a robust understanding of their structure be developed. However, high-resolution transmission electron microscopy (HR-TEM) imaging of such beam-sensitive materials is an outstanding characterization challenge. Here, we overcome this challenge by leveraging low electron flux imaging conditions and high-speed direct electron counting detectors to acquire high-resolution images of 2D COF films. We developed a Fourier mapping technique to rapidly extract nanoscale structural information from these TEM images. This postprocessing script analyzes the evolution of 2D Fourier transforms across a TEM image, which yields information about polycrystalline domain orientations and enables quantification of average domain sizes. Moreover, this approach provides information about several types of defects present in a film, such as overlapping grains and various types of grain boundaries. We also find that the pre-eminent origin of defects in COF-5 films, a prototypical boronate ester-linked COF, arises as a consequence of broken B-O bonds formed during polymerization. These results suggest that the nanoscale features observed are a direct consequence of chemical phenomena. Taken together, this mapping approach provides information about the fundamental microstructure and crystallographic underpinnings of 2D COF films, which will guide the development of future 2D polymerization strategies and help realize the goal of using 2D COFs in a host of thin-film device architectures.

Summary We directly initiate and visualize the formation of polymeric nanomaterials via variable-temperature liquid-cell transmission electron microscopy (VT-LCTEM). With temperature control in the liquid cell, reversible addition-fragmentation chain transfer polymerization was thermally initiated, leading to the formation of amphiphilic block copolymers that assemble upon dispersion polymerization-induced self-assembly (PISA). In combination with traditional ex situ analyses, VT-LCTEM enabled not only the characterization of the nanoparticles in situ but also the observation of a thermal phase transition. Critically, because these assemblies form from thermoresponsive components, any temperature changes during sample preparation and analysis can alter morphologies, necessitating direct in situ characterization of reaction progression. We believe that the findings and the technique described herein will lead to unprecedented possibilities for the development and characterization of self-organizing soft matter.

International audience; Interpenetration of two or more sublattices is common among many metal–organic frameworks (MOFs). Herein, we study the evolution of one zirconium cluster-based, 3,8-connected MOF from its non-interpenetrated (NU-1200) to interpenetrated (STA-26) isomer. We observe this transient catenation process indirectly using ensemble methods, such as nitrogen porosimetry and X-ray diffraction, and directly, using high-resolution transmission electron microscopy. The approach detailed here will serve as a template for other researchers to monitor the interpenetration of their MOF samples at the bulk and single-particle limits. We investigate the mechanical stability of both lattices experimentally by pressurized in situ X-ray diffraction and nanoindentation as well as computationally with density functional theory calculations. Both lines of study reveal that STA-26 is considerably more mechanically stable than NU-1200. We conclude this study by demonstrating the potential of these MOFs and their mixed phases for the capture of gaseous n-hexane, used as a structural mimic for the chemical warfare agent sulfur mustard gas.