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Single-chain polymer nanoparticles (SCNPs) are soft nano-objects consisting of uni-macromolecular chains collapsed to a certain degree by intramolecular crosslinking. The similarities between the behaviour of SCNPs and that of intrinsically disordered proteins suggest that SCNPs in concentrated solutions can be used as models to design artificial micro-environments, which mimic many of the general aspects of cellular environments. In this work, the self-assembly into SCNPs of an amphiphilic random copolymer, composed by oligo(ethylene glycol)methyl ether methacrylate (OEGMA) and 2-acetoacetoxy ethyl methacrylate (AEMA), has been investigated by means of the dielectric relaxation of water. Direct evidence of segregation of the AEMA repeating units is provided by comparison with the dielectric relaxation of water in similar solutions of the linear hydrophilic polymer, P(OEGMA). Furthermore, the results of comparative studies with similar water solutions of an amphiphilic block copolymer forming multi-chain micelles support the single-chain character of the self-assembly of the random copolymer. The overall obtained results highlight the suitability of the dielectric spectroscopy to confirm the self-assembly of the amphiphilic random copolymers into globular like core-shell single-chain nanoparticles at a concentration well above the overlap concentration.

Access to completely deuterated single-chain nanoparticles (dSCNPs) has remained an unresolved issue. Herein, the first facile and efficient procedure to produce dSCNPs is reported, which comprises: i) the use of commercially available perdeuterated cyclic ether monomers as starting reagents, ii) a ring-opening copolymerization process performed in bulk to produce a neat dSCNP precursor, iii) a standard azidation reaction to decorate this precursor with azide moieties, and iv) a facile intramolecular azide photodecomposition step carried out under UV irradiation at high dilution providing with highly valuable, completely deuterated soft nano-objects from the precursor. dSCNPs are used to investigate by means of neutron-scattering measurements the form factor (radius of gyration, scaling exponent) of polyethylene oxide (PEO) chains in nanocomposites with different amounts of dSCNPs. Moreover, to illustrate the possibilities offered by the synthetic route disclosed in this communication for potential applications, the significant reduction in viscosity observed in a pure melt of polyether-based single-chain nanoparticles when compared to a melt of the corresponding linear polymer chains is shown., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

By means of large-scale computer simulations and small-angle neutron scattering (SANS), we investigate solutions of single-chain nanoparticles (SCNPs), covering the whole concentration range from infinite dilution to melt density. The analysis of the conformational properties of the SCNPs reveals that these synthetic nano-objects share basic ingredients with intrinsically disordered proteins (IDPs), as topological polydispersity, generally sparse conformations, and locally compact domains. We investigate the role of the architecture of the SCNPs in their collapse behavior under macromolecular crowding. Unlike in the case of linear macromolecules, which experience the usual transition from self-avoiding to Gaussian random-walk conformations, crowding leads to collapsed conformations of SCNPs resembling those of crumpled globules. This behavior is already found at volume fractions (about 30%) that are characteristic of crowding in cellular environments. The simulation results are confirmed by the SANS experiments. Our results for SCNPs--a model system free of specific interactions--propose a general scenario for the effect of steric crowding on IDPs: collapse from sparse conformations at high dilution to crumpled globular conformations in cell environments.

The control of primary and further structures of individual folded/collapsed synthetic polymers has received significant attention in recent years. However, the synthesis of single-chain nanoparticles (SCNPs) showing a compact, globular conformation in solution has turned out so far to be highly elusive. By means of simulations, we propose two methods for obtaining globular SCNPs in solution. The first synthesis route is performed in the bad solvent, with the precursor anchored to a surface. In the second route we use a random copolymer precursor with unreactive solvophilic and reactive solvophobic units, which form a single core-shell structure. Both protocols prevent intermolecular cross-linking. After recovering good solvent conditions, the swollen nanoparticles maintain their globular character. The proposed methods are experimentally realizable and do not require specific sequence control of the precursors. Our results pave the way for the synthesis via solvent-assisted design of a new generation of globular soft nanoparticles mimicking global conformations of native proteins in solution.

Inspired by the multifunctionality of vitamin D-binding protein and the multiple transient-binding behavior of some intrinsically disordered proteins (IDPs), a polymeric platform is designed, prepared, and characterized for combined delivery of dermal protective and anticancer bioactive cargos on the basis of artificial single-chain nano-objects mimicking IDPs. For the first time ever, simultaneous delivery of folic acid or vitamin B9 , and hinokitiol, a relevant natural bioactive compound that exhibits anticancer activity against human malignant melanoma cells, from these multidirectionally self-assembled unimolecular nanocarriers is illustrated., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The impact of purely intramolecular cross-linking on the properties of a polymer melt is studied by neutron diffraction and quasielastic incoherent and coherent neutron scattering on a system composed exclusively of single-chain nanoparticles. As a reference, a parallel study is presented on the melt of the linear precursor chains' counterpart. Associated with structural heterogeneities provoked by the internal compartmentalization due to cross-links, a dramatic slowing down of the relaxation of density fluctuations is observed at intermediate length scales. [ABSTRACT FROM AUTHOR]

The folding/collapse of linear single chains to single-chain nanoparticles (SCNPs) is a field of intense activity. Current synthetic methods allow obtaining from sparse SCNP morphologies in solution - resembling those observed in intrinsically disordered proteins - to compact SCNP conformations, more akin to those displayed by globular enzymes. A useful characterization technique in the field of SCNPs is 'conventional' size-exclusion chromatography (SEC) with differential refractive index (DRI) detection, providing rapid and convincing evidence of SCNP formation through comparison of the SEC traces of the precursor and the SCNPs. Upon SCNP formation, a noticeable shift of the SEC curve toward longer retention times (i.e., lower hydrodynamic sizes) is observed. However, quantitative information embedded in the SEC curve about the actual 'compaction degree' of the SCNPs has not yet been extracted to distinguish between sparse and globular SCNPs. Here, a useful methodology for quantifying the compaction degree of SCNPs by SEC with conventional DRI detector is introduced allowing: i) construction of theoretical SEC curves corresponding to the collapse of a linear precursor having a log-normal molecular weight distribution to either sparse or globular SCNPs and ii) analysis of experimental SEC curves to estimate the actual morphology of synthetic SCNPs in solution. [ABSTRACT FROM AUTHOR]

Controlling the spatial distribution of catalytic sites in metallo-folded single-chain nanoparticles (SCNPs) is a first step toward the rational design of improved catalytic soft nanoobjects. Here an unexplored pathway is reported for tuning the internal structure of metallo-folded SCNPs. Unlike the conventional SCNP synthesis in good solvent (protocol I), the proposed new route (protocol II) is based on the use of amphiphilic random copolymers and transfer, after SCNP formation, from selective to good (nonselective) solvent conditions. The size and morphology of the SCNPs obtained by the two protocols, and the corresponding spatial distribution of the catalytic sites, have been determined by combining results from size exclusion chromatography with triple detection, small-angle X-ray scattering and molecular dynamics (MD) simulations. Remarkably, the use of these protocols allows the tuning of the internal structure of the metallo-folded SCNPs, as supported by MD simulations results. While the conventional protocol I yields a homogeneous distribution of the catalytic sites in the SCNP, these are arranged into clusters in the case of protocol II. [ABSTRACT FROM AUTHOR]

Endowing unimolecular soft nanoobjects with biomimetic functions is attracting significant interest in the emerging field of single-chain technology. Inspired by the compartmentalized structure and polymerase activity of metalloenzymes, copper-containing compact nanoglobules have been designed, synthesized, and characterized endowed with metalloenzyme mimicking characteristics toward controlled synthesis of water-soluble polymers and thermoresponsive hydrogels. When compared to metalloenzymes, artificial nanoobjects endowed with metalloenzyme mimicking characteristics offer increased stability against thermal changes and reduced degradability by hydrolytic enzymes. [ABSTRACT FROM AUTHOR]

We present a combined study by quasielastic neutron scattering (QENS), dielectric and mechanical spectroscopy, calorimetry and wide-angle X-ray diffraction on single-chain nano-particles (SCNPs), using the corresponding linear precursor chains as reference, to elucidate the impact of internal bonds involving bulky cross-links on the properties of polymer melts. Internal cross-links do not appreciably alter local properties and fast dynamics. This is the case of the average inter-molecular distances, the β-relaxation and the extent of the atomic displacements at timescales faster than some picoseconds. Contrarily, the α-relaxation is slowed down with respect to the linear precursor, as detected by DSC, dielectric spectroscopy and QENS. QENS has also resolved broader response functions and stronger deviations from Gaussian behavior in the SCNPs melt, hinting at additional heterogeneities. The rheological properties are also clearly affected by internal cross-links. We discuss these results together with those previously reported on the deuterated counterpart samples and on SCNPs obtained through a different synthesis route to discern the effect of the nature of the cross-links on the modification of the diverse properties of the melts. [ABSTRACT FROM AUTHOR]

The folding of certain proteins (e.g., enzymes) into perfectly defined 3D conformations via multi-orthogonal interactions is critical to their function. Concerning synthetic polymers chains, the "folding" of individual polymer chains at high dilution via intra-chain interactions leads to so-called single-chain nanoparticles (SCNPs). This review article describes the advances carried out in recent years in the folding of single polymer chains into discrete SCNPs via multi-orthogonal interactions using different reactive chemical species where intra-chain bonding only occurs between groups of the same species. First, we summarize results from computer simulations of multi-orthogonally folded SCNPs. Next, we comprehensively review multi-orthogonally folded SCNPs synthesized via either non-covalent bonds or covalent interactions. Finally, we conclude by summarizing recent research about multi-orthogonally folded SCNPs prepared through both reversible (dynamic) and permanent bonds. [ABSTRACT FROM AUTHOR]

Front Cover: Guided by molecular dynamics simulation tools, single‐chain polymer nanocarriers mimicking disordered proteins are prepared under optimized experimental conditions. Of special novelty and practical interest is the combined delivery of dermal protective (folic acid) and anticancer (hinokitiol) bioactive cargos from these artificial single‐chain nano‐objects in a pH‐dependent manner. Further details can be found in the article by A. Sanchez‐Sanchez, S. Akbari, A. J. Moreno, F. Lo Verso, A. Arbe, J. Colmenero, and J. A. Pomposo* on page 1681. [ABSTRACT FROM AUTHOR]

Single-chain polymer nanoparticles (SCNPs) are individual intrachain cross-linked polymer chains -typically with a size < 20 nm-which can be considered as emerging building blocks for bionanotechnology. Very recently, surfaces displaying molecular recognition motifs have been decorated with brushes of responsive SCNPs and transformed into a cross-linked polymeric monolayer, thus paving the way to controlled nanofilm formation around bioactive surfaces (e.g. , virus capsids). In this work, the structural properties of brushes formed by topologically complex SCNPs on flat surfaces are investigated as a function of SCNP size and intrachain cross-linking degree. A detailed comparison is performed to the structural features displayed by brushes of other macromolecular architectures, thus revealing the tunable, unique properties of brushes comprising elastic SCNPs. Remarkably, this work paves the way to the potential design of brushes of SCNPs with drug delivery characteristics based on stimulus-mediated rupture of intrachain cross-links. Image 1 • Brushes formed by elastic SCNPs on flat surfaces are investigated. • The SCNP intrachain crosslinking degree is an additional parameter to control brush thickness. • An increase in brush thickness is observed upon breaking of intrachain crosslinks. [ABSTRACT FROM AUTHOR]

We present an investigation by combining small-angle neutron scattering (SANS) and coarse-grained molecular dynamics (MD) simulations on the conformational properties of single-chain nanoparticles (SCNPs) in crowded macromolecular solutions. By using linear chains as crowders, SANS shows a crossover from almost unperturbed SCNP conformations in dilute conditions toward a continuous collapse of the macromolecule with increasing crowding. This collapse starts when the total concentration of the solution reaches the value of the overlap concentration of the pure SCNP solutions. MD simulations suggest the generalizability of these experimental findings and extend them to the case when the SCNPs themselves are used as crowders—a situation which in real systems leads to unavoidable formation of aggregates, as shown here by SANS and DLS. Exploiting the simulations, we have calculated the contact probability and the distance between monomers as functions of the contour distance between them; the results suggest that crumpled globular conformations are generally adopted by SCNPs in crowded macromolecular solutions. In the case of linear crowders, the SCNPs show, at fixed monomer concentration, a nonmonotonic dependence of their collapse on the length of the crowders. [ABSTRACT FROM AUTHOR]

Single-chain nanoparticles (SCNPs) constructed via reversible bonds are versatile stimuli-responsive soft nano-objects with potential use in nanomedicine, bioimaging, biosensing, and catalysis applications. In recent years, many different types of reversible SCNPs have been reported involving intrachain hydrogen bonding, host-guest interactions, and metal complex formation, among other reversible bonds. As illustrated in this work, reversible SCNPs in solution with similar nature, molar mass, and amount of reactive groups than irreversible (covalent-bonded) SCNPs display, on average, a lower level of chain compaction. We follow herein a Flory-like argument to obtain a simple expression providing the expected size reduction upon folding single chains of size R0 to SCNPs of size R with reversible interactions. Accurate estimation of R is of outmost importance for developing practical applications of responsive SCNPs based on structure-property relationships. For precursor chains having a fraction of groups x involved in reversible bonds, the expected size upon intrachain folding of the precursor chains to conventional SCNPs is given by R = R0(1 - x)0.6. We perform a comparison of the size reduction predicted by the former expression with extensive literature data for SCNPs constructed via reversible bonds (72 SCNPs, 22 reversible interactions). The overall agreement between theoretical and experimental data is excellent, hence allowing a valuable a priori estimation of the size reduction upon folding single chains to single-chain nanoparticles via reversible interactions. [ABSTRACT FROM AUTHOR]

The incorporation of high-molecular-weight poly(ethylene oxide) (PEO) in the nanopores of resorcinol-formaldehyde resin nanoparticles (RNPs) leads to the suppression of polymer crystallization, changes in the chain conformation, and a noticeable slowdown of the two dielectric relaxations that reflect the segmental and local PEO dynamics. Both relaxations are significantly slower than those corresponding to bulk PEO. These results are independent of the pore characteristics of the different RNP materials. The segmental relaxation shows a crossover at ca. 220 K in its temperature dependence from non-Arrhenius to Arrhenius-like behavior on cooling. These results suggest the occurrence of limited cooperativity at low temperatures due to the enhancement of long-living hydrogen bonding between PEO and RNP pore walls. [ABSTRACT FROM AUTHOR]

Weinvestigate, by means of computer simulations, the formationof soft nanoparticles by irreversible intramolecular cross-linkingof homofunctional polymer precursors in good solvent. Simulationsreveal that the early and intermediate stages of the cross-linkingprocess are dominated by bonding at short contour distances. Becauseof the initial self-avoiding character of the precursor, bonding atlong contour distances, which is the efficient mechanism for globalcompactation, is a rare event that essentially occurs in the latestage of cross-linking. Thus, irreversible cross-linking of precursorswith identical molecular weight and linker fraction produces bothcompact and sparse objects. This is confirmed by a detailed analysisof the size and shape distribution of the fully cross-linked nanoparticles.We also investigate intramolecular cross-linking of heterofunctionalpolymers with two species of orthogonal linkers, bonding between distinctspecies being forbidden. It is found that simultaneous cross-linkingof both species and sequential cross-linking (activation of one speciesafter full cross-linking of the other) lead to the same structuralproperties for the resulting nanoparticles. The heterofunctional nanoparticlesare on average smaller and more spherical than the homofunctionalcounterparts, though still a significant fraction of sparse objectsis found. The simulation results are compared with results from SEC/MALLSand SAXS experiments in real polymeric nanoparticles. [ABSTRACT FROM AUTHOR]

Abstract: The physical aging process, namely the spontaneous evolution of the thermodynamic state occurring in glasses, has been monitored in poly(methyl methacrylate) (PMMA)/silica and polystyrene (PS)/silica nanocomposites following the time evolution of the enthalpy by means of differential scanning calorimetry (DSC). The effect on physical aging of the content of silica particles has been investigated in detail varying it over a wide range. Our results indicate accelerated physical aging in the nanocomposites in comparison to the corresponding pure polymer. Furthermore the acceleration is generally more pronounced in nanocomposites presenting a high silica content. This result cannot be attributed to a difference in molecular mobility of the polymers in the nanocomposites in comparison to pure PMMA and PS, since broadband dielectric spectroscopy (BDS) indicates no effect of silica nanoparticles on the polymer segmental dynamics. Moreover, calorimetric measurements reveal a reduction of the heat capacity jump at Tg for the nanocomposites, as well as lower experimentally recoverable enthalpy values. This may result from the faster non-isothermal evolution of the glass state when cooling down the samples from their liquid state. To account for these experimental results the acceleration of physical aging has been rationalized in the framework of the diffusion of free volume holes model as previously proposed. This is able to adequately catch the dependence of the physical aging rate on silica content, determining the area of nanoparticles to the volume of polymer, that is the relevant variable within the diffusion model. [Copyright &y& Elsevier]