Why Single-Chain Nanoparticles from Weak Polyelectrolytes Can Be Synthesized at Large Scale in Concentrated Solution?

Here, the unresolved question of why single-chain nanoparticles (SCNPs) prepared from a weak polyelectrolyte (PE) precursor can be synthesized on a large is addresses, unlike SCNPs obtained from an equivalent neutral (nonamphiphilic) polymer precursor. The combination of the standard elastic single-chain nanoparticles (ESN) model -developed for neutral chains- with the classical scaling theory of PE solutions provides the key. Essentially, the long-range repulsion between electrostatic blobs in a weak PE precursor restricts the cross-linking process during SCNPs formation to the interior of each blob. Consequently, the maximum concentration at which PE-SCNPs can be prepared without interchain cross-linking is not determined by the full size of the PE precursor but, instead, by the smaller size of its electrostatic blobs. Therefore, PE-SCNPs can be synthesized up to a critical concentration where electrostatic blobs from different chains touch each other. This concentration can be 30 times higher than that for non-PE polymer precursors. Upon progressive dilution, the size of PE-SCNPs synthesized in concentrated solution increases until it reaches the bigger size of PE-SCNPs prepared under highly diluted conditions. PE-SCNPs do not adopt a globular conformation either in concentrated or in diluted solution. It shows that the main model predictions agree with experimental results.

Lanthanide-Based Single-Chain Nanoparticles as "Visual" Pass/Fail Sensors of Maximum Permissible Concentration of Cu2+ Ions in Drinking Water.

The maximum permissible concentration (m.p.c.) of Cu2+ ions in drinking water, as set by the World Health Organization (WHO) is m.p.c. (Cu2+)WHO = 30 × 10-6 m, whereas the US Environmental Protection Agency (EPA) establishes a more restrictive value of m.p.c. (Cu2+)EPA = 20 × 10-6 m. Herein, for the first time ever, a family of m.p.c. (Cu2+) "visual" pass/fail sensors is developed based on water-soluble lanthanide-containing single-chain nanoparticles (SCNPs) exhibiting an average hydrodynamic diameter less than 10 nm. Both europium (Eu)- and terbium (Tb)-based SCNPs allow excessive Cu2+ to be readily detected in water, as indicated by the red-to-transparent and green-to-transparent changes, respectively, under UV light irradiation, occurring at 30 × 10-6 m Cu2+ in both cases. Complementary, dysprosium (Dy)-based SCNPs show a yellow color-to-transparent transition under UV light irradiation at ≈15 × 10-6 m Cu2+. Eu-, Tb-, and Dy-containing SCNPs prove to be selective for Cu2+ ions as they do not respond against other metal ions, such as Fe2+, Ag+, Co2+, Ba2+, Ni2+, Hg2+, Pb2+, Zn2+, Fe3+, Ca2+, Mn2+, Mg2+, or Cr3+. These new m.p.c. (Cu2+) "visual" pass/fail sensors are thoroughly characterized by a combination of techniques, including size exclusion chromatography, dynamic light scattering, inductively coupled plasma-mass spectrometry, as well as infrared, UV, and fluorescence spectroscopy.

Ultrasmall Single-Chain Nanoparticles Derived from Amphiphilic Alternating Copolymers.

The collapse or folding of an individual polymer chain into a nanoscale particle gives rise to single-chain nanoparticles (SCNPs), which share a soft nature with biological protein particles. The precise control of their properties, including morphology, internal structure, size, and deformability, are a long-standing and challenging pursuit. Herein, a new strategy based on amphiphilic alternating copolymers for producing SCNPs with ultrasmall size and uniform structure is presented. SCNPs are obtained by folding the designed alternating copolymer in N,N-dimethylformamide (DMF) and fixing it through a photocatalyzed cycloaddition reaction of anthracene units. Molecular dynamics simulation confirms the solvophilic outer corona and solvophobic inner core structure of SCNPs. Furthermore, by adjusting the length of PEG units, precise control over the mean size of SCNPs is achieved within the range of 2.8 to 3.9 nm. These findings highlight a new synthetic strategy that enables enhanced control over morphology and internal structure while achieving ultrasmall and uniform size for SCNPs.

Quasi-Chromophores Segregated by Single-Chain Nanoparticles of Fluorinated Zwitterionic Random Copolymers Showing Remarkably Enhanced Fluorescence Emission Capable of Fluorescent Cell Imaging.

Organic and polymer fluorescent nanomaterials are a frontier research focus. Here in this work, a series of fluorinated zwitterionic random copolymers end-attached with a quasi-chromophoric group of pyrene or tetraphenylethylene (TPE) are well synthesized via atom transfer radical polymerization with activators regenerated by electron transfer (ARGET ATRP). Those random copolymers with total degree of polymerization 100 or 200 are able to produce fluorescent single-chain nanoparticles (SCNPs) through intra-chain self-folding assembly with quite uniform diameters in the range of 10-20 nm as characterized by dynamic light scattering and transmission electron microscopy. By virtue of the segregation or confinement effect, both SCNPs functionalized with pyrene or TPE group are capable of emitting fluorescence, with pyrene tethered SCNPs exhibiting stronger fluorescence emission reaching the highest quantum yield ≈20%. Moreover, such kind of fluorescent SCNPs manifest low cytotoxicity and good cell imaging performance for Hela cells. The creation of fluorescent SCNPs through covalently attached one quasi-chromophore to the end of one fluorinated zwitterionic random copolymer provides an alternative strategy for preparing polymeric luminescence nanomaterials, promisingly serving as a new type of fluorescent nanoprobes for biological imaging applications.

Single Chain Nanoparticles in Catalysis.

Over the last six decades folded polymer chains-so-called Single Chain Nanoparticles (SCNPs)-have evolved from the mere concept of intramolecularly crosslinked polymer chains to tailored nanoreactors, underpinned by a plethora of techniques and chemistries to tailor and analyze their morphology and function. These monomolecular polymer entities hold critical promise in a wide range of applications. Herein, we highlight the exciting progress that has been made in the field of catalytically active SCNPs in recent years.

Tuning the Internal Compartmentation of Single-Chain Nanoparticles as Fluorescent Contrast Agents.

Controlling the internal structures of single-chain nanoparticles (SCNPs) is an important factor for their targeted chemical design and synthesis, especially in view of nanosized compartments presenting different local environments as a main feature to control functionality. We here design SCNPs bearing near-infrared fluorescent dyes embedded in hydrophobic compartments for use as contrast agents in pump-probe photoacoustic (PA) imaging, displaying improved properties by the location of the dye in the hydrophobic particle core. Compartment formation is controlled via single-chain collapse and subsequent crosslinking of an amphiphilic polymer using external crosslinkers in reaction media of adjustable polarity. Different SCNPs with hydrodynamic diameters of 6-12 nm bearing adjustable label densities are synthesized. It is found that the specific conditions for single-chain collapse have a major impact on the formation of the desired core-shell structure, in turn adjusting the internal nanocompartments together with the formation of excitonic dye couples, which in turn increase their fluorescence lifetime and PA signal generation. SCNPs with the dye molecules accumulate at the core also show a nonlinear PA response as a function of pulse energy-a property that can be exploited as a contrast mechanism in molecular PA tomography.

Metamorphosis of a Commodity Plastic like PVC to Efficient Catalytic Single-Chain Nanoparticles.

We perform the conversion of a commodity plastic of common use in pipes, window frames, medical devices, flexible hoses, etc. like polyvinyl chloride (PVC) to single-chain nanoparticles (SCNPs). SCNPs are versatile, protein-mimetic soft nano-objects of growing interest for catalysis, sensing, and nanomedicine, among other uses. We demonstrate that the metamorphosis process -as induced through metal-free click chemistry- leads to well-defined, uniform SCNPs that are stable during storage in the solid state for months. All the conversion process (from PVC isolation to PVC-SCNPs synthesis) can be run in a green, dipolar aprotic solvent and involving, when required, a simple mixture of ethanol and water (1/1 vol.) as non-solvent. The resulting PVC-SCNPs are investigated as recyclable, metalloenzyme-mimetic catalysts for several representative Cu(II)-catalyzed organic reactions. The method could be valid for the metamorphosis and valorization of other commodity plastics in which it is feasible to install azide functional groups in their linear polymer chains.

Visible-Light-Induced Control over Reversible Single-Chain Nanoparticle Folding.

We introduce a class of single-chain nanoparticles (SCNPs) that respond to visible light (λmax =415 nm) with complete unfolding from their compact structure into linear chain analogues. The initial folding is achieved by a simple esterification reaction of the polymer backbone constituted of acrylic acid and polyethylene glycol carrying monomer units, introducing bimane moieties, which allow for the photochemical unfolding, reversing the ester-bond formation. The compaction and the light driven unfolding proceed cleanly and are readily followed by size exclusion chromatography (SEC) and diffusion ordered NMR spectroscopy (DOSY), monitoring the change in the hydrodynamic radius (RH ). Importantly, the folding reaction and the light-induced unfolding are reversible, supported by the high conversion of the photo cleavage. As the unfolding reaction occurs in aqueous systems, the system holds promise for controlling the unfolding of SCNPs in biological environments.

Preparation of AIE Functional Single-Chain Polymer Nanoparticles and Their Application in H2 O2 Detection through Intermolecular Heavy-Atom Effect.

Single-chain polymer nanoparticles (SCNPs) are soft matter constructed by intrachain crosslinks, with promising prospects in detection and catalysis. Herein, a fluorescent core (SCNPs) with aggregation-induced emission (AIE) is prepared, applying for H2 O2 detection through intermolecular heavy-atom effect. In detail, the SCNPs precursors are synthesized by ring-opening copolymerization. Then the SCNPs are prepared by intramolecularly cross-linking via olefin metathesis. Imitating the structure of AIE dots, SCNPs are encapsulated by H2 O2 -responsive polymers. Probably due to the stable secondary structure of SCNPs, the obtained micelles show stable fluorescence performance. Furthermore, as the heavy-atom, tellurium is introduced into the carriers to construct the heavy-atom effect. In this micelle-based system, the SCNPs act as the fluorescent core, and the stimuli-responsive polymer acts as the carrier and the fluorescent switch. The hydrophilicity of the tellurium-containing segment is affected by the concentration of H2 O2 , resulting in a change in the distance from the SCNPs, which ultimately leads to a change in the fluorescence intensity. Furthermore, tellurium is particularly sensitive to H2 O2 , which can detect low concentrations of H2 O2 . The SCNPs are merged with AIE materials, with the hope of exploring new probe designs.

Solvent Remodeling in Single-Chain Amphiphilic Heteropolymer Systems.

This work demonstrates the remodeling of single-chain nanoparticles (SCNPs) upon a transition to organic solvent through molecular dynamics simulations. Methacrylate-based random heteropolymers (RHPs), assembled via transient noncovalent linkages in water, have shown promise in an assortment of applications that harness their bio-inspired properties. While their molecular behavior has been broadly characterized in aqueous environments, many newer applications include the use of organic solvent rather than bio-mimetic conditions. The polymer assemblies, typically driven by the hydrophobic effect in water, are less well understood in nonaqueous solution. Here, a specific RHP system is examined which forms compact globular morphologies in highly polar or highly nonpolar environments while adopting extended conformations in solvents of intermediate polarity. The pivotal role of electrostatic interactions between charge groups in low dielectric mediums is also observed. Finally, high temperature anneal cycles are compared to room temperature transformations to illuminate barriers to remodeling upon environmental changes.

Scalable Synthesis of Photoluminescent Single-Chain Nanoparticles by Electrostatic-Mediated Intramolecular Crosslinking.

We report the large-scale synthesis of photoluminescent single-chain nanoparticles (SCNPs) by electrostatic-mediated intramolecular crosslinking in a concentrated solution of 40 mg mL-1 by continuous addition of the free radical initiator. Poly(vinyl benzyl chloride) was charged by quaternization with vinyl-imidazolium for the intramolecular crosslinking by using 2,2-dimethoxy-2-phenylacetophenone (DMAP) as the radical initiator. Under the electrostatic repulsion thus interchain isolation, the intrachain crosslinking experiences the transition from coil through pearl-necklace to globular state. The SCNPs demonstrate strong photoluminescence in the visible range when the non-emissive units are confined thereby. Composition and microstructure of the SCNPs are tunable. The photoluminescent tadpole-like Janus SCNP can be used to selectively illuminate interfacial membranes while stabilizing the emulsions.

Self-Reporting of Folding and Aggregation by Orthogonal Hantzsch Luminophores Within a Single Polymer Chain.

Self-reporting fluorescence methods for monitoring folding and aggregation of proteins have a long history in biochemistry. Placing orthogonal luminophores within individual synthetic polymer chains for self-reporting both folding (i.e., its intramolecular compaction to isolated single-chain nanoparticles, SCNPs) and unbidden aggregation (i.e., the intermolecular association of SCNPs) remains a great challenge. Herein, a simple and efficient platform to identify both single-chain compaction and intermolecular aggregation phenomena via photoluminescence is presented based on simultaneous synthesis through Hantzsch ester formation of orthogonal luminophores within the same polymer chain. Starting from non-luminescent ß-ketoester-decorated chains, intramolecular compaction is visually detected through fluorescence arising from Hantzsch fluorophores generated as intra-chain connectors during folding. Complementary, intermolecular association is identified via aggregation-induced emission (AIE) from orthogonal luminophores displaying intense photoluminescence at redshifted wavelengths after formation of multi-SCNPs assemblies.

Fluorescent and Water Dispersible Single-Chain Nanoparticles: Core-Shell Structured Compartmentation.

Single-chain nanoparticles (SCNPs) are highly versatile structures resembling proteins, able to function as catalysts or biomedical delivery systems. Based on their synthesis by single-chain collapse into nanoparticular systems, their internal structure is complex, resulting in nanosized domains preformed during the crosslinking process. In this study we present proof of such nanocompartments within SCNPs via a combination of electron paramagnetic resonance (EPR) and fluorescence spectroscopy. A novel strategy to encapsulate labels within these water dispersible SCNPs with hydrodynamic radii of ≈5 nm is presented, based on amphiphilic polymers with additional covalently bound labels, attached via the copper catalyzed azide/alkyne "click" reaction (CuAAC). A detailed profile of the interior of the SCNPs and the labels' microenvironment was obtained via electron paramagnetic resonance (EPR) experiments, followed by an assessment of their photophysical properties.

One-Shot Intrablock Cross-Linking of Linear Diblock Copolymer to Realize Janus-Shaped Single-Chain Nanoparticles.

Developing an efficient and versatile process to transform a single linear polymer chain into a shape-defined nanoobject is a major challenge in the fields of chemistry and nanotechnology to replicate sophisticated biological functions of proteins and nucleic acids in a synthetic polymer system. In this study, we performed one-shot intrablock cross-linking of linear block copolymers (BCPs) to realize single-chain nanoparticles (SCNPs) with two chemically compartmentalized domains (Janus-shaped SCNPs). Detailed structural characterizations of the Janus-shaped SCNP composed of polystyrene-block-poly(glycolic acid) revealed its compactly folded conformation and compartmentalized block localization, similar to the self-folded tertiary structures of natural proteins. Versatility of the one-shot intrablock cross-linking was demonstrated using several different BCP precursors. In addition, the Janus-shaped SCNP produce miniscule microphase-separated structures.

Synthesis of Polymer Single-Chain Nanoparticle with High Compactness in Cosolvent Condition: A Computer Simulation Study.

Polymeric single-chain nanoparticles (SCNPs) are soft nano-objects synthesized by intramolecular crosslinking of isolated single polymer chains. Syntheses of such SCNPs usually need to be performed in a dilute solution. In such a condition, the bonding probability of the two active crosslinking units at a short contour distance along the chain backbone is much higher than those which are far away from each other. Such a reaction condition often results in local spheroidization and, therefore, the formation of loosely packed structures. How to inhibit the local spheroidization and improve the compactness of SCNPs is thus a major challenge for the syntheses of SCNPs. In this study, computer simulations are performed and the fact that a precollapse of the polymer chain conformation in a cosolvent condition can largely improve the probability of the crosslinking reactions at large contour distances is demonstrated, favoring the formations of closely packed globular structures. As a result, the formed SCNPs can be more spherical and have higher compactness than those fabricated in ultradilute good solvent solution in a conventional way. It is believed this simulation work can provide a insight into the effective syntheses of SCNPs with spherical conformations and high compactness.

Wavelength-Selective Folding of Single Polymer Chains with Different Colors of Visible Light.

Photochemistry allows chemists to exert control over chemical reactions with spatiotemporal precision. Furthermore, light holds the potential to not only gate when and where but also which reaction takes place. Herein, two photocycloaddition reactions-initiated by different colors of visible light-are utilized to control the intramolecular crosslinking of single polymer chains. Irradiation with blue light (λmax = 470 nm) triggers a [2 + 2] photocycloaddition inducing an initial intramolecular crosslinking reaction, whereas subsequent irradiation with violet light (λmax = 415 nm) induces a [4 + 4] photocycloaddition, fully compacting the dual photoreactive polymer into a single-chain nanoparticle. Importantly, both crosslinked states are accessible under ultra-mild conditions requiring nothing but two different colors of visible light. The reported strategy of wavelength-selective crosslinking degrees provides key potential to be translated into materials applications for the remote control of mechanical properties on the molecular level.

CO2 -Folded Single-Chain Nanoparticles as Recyclable, Improved Carboxylase Mimics.

Emulating the function of natural carboxylases to convert CO2 under atmospheric condition is a great challenge. Herein we report a class of CO2 -folded single-chain nanoparticles (SCNPs) that can function as recyclable, function-intensified carboxylase mimics. Lewis pair polymers containing bulky Lewis acidic and basic groups as the precursor, can bind CO2 to drive an intramolecular folding into SCNPs, in which CO2 as the folded nodes can form gas-bridged bonds. Such bridging linkages highly activate CO2 , which endows the SCNPs with extraordinary catalytic ability that can not only catalyze CO2 -insertion of C(sp3 )-H for imitating the natural enzyme's function, it can also act on non-natural carboxylation pathways for C(sp2 and sp)-H substrates. The nanocatalysts are of highly catalytic efficiency and recyclability, and can work at room temperature and near ambient CO2 condition, inspiring a new approach to sustainable C1 utilization.

Catalytically Active N-Heterocyclic Carbene Release from Single-Chain Nanoparticles Following a Thermolysis-Driven Unfolding Strategy.

The need for efficient, tailor-made catalysts has inspired chemists to design synthetic macromolecular architectures for selective catalysis. To this purpose, herein the synthesis and in-depth characterization of Ag(I)-crosslinked single-chain nanoparticles (SCNPs) is reported and their application as catalysts is demonstrated. Specifically, a copolymer of styrenic benzimidazolium chloride is synthesized as a linear precursor via reversible addition-fragmentation chain-transfer polymerization. Metalation of the benzimidazolium moieties by Ag(I) resulted in the intramolecular cross-linking of single chains via the formation of silver-N-heterocyclic carbene (Ag-NHC) linkages under dilute conditions. The successful formation of well-defined, robust SCNPs is evidenced by size-exclusion chromatography, dynamic light scattering, nuclear magnetic resonance spectroscopy, and transmission electron microscopy. Finally, it is demonstrated that the Ag-SCNPs can be used as NHC pre-catalysts, by first indirectly evidencing the formation of the corresponding unfolded NHC-CS2 polybetaine and then organocatalysing a benzoin condensation reaction.

Facile Access to Completely Deuterated Single-Chain Nanoparticles Enabled by Intramolecular Azide Photodecomposition.

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.

Synthesis of Single-Ring Nanoparticles Mimicking Natural Cyclotides by a Stepwise Folding-Activation-Collapse Process.

Cyclotides are small cyclic polypeptides found in a variety of organisms, ranging from bacteria to plants. Their ring structure endows those polypeptides with specific properties, such as improved stability against enzymatic degradation. Optimal cyclotide activity is often observed only in the presence of intra-ring disulfide bonds. Synthesis of soft nano-objects mimicking the conformation of natural cyclotides remains challenging. Here, a new class of natural cyclotide mimics synthesized by a stepwise folding-activation-collapse process at high dilution starting from simple synthetic precursor polymers is established. The initial folding step is carried out by a photoactivated hetero Diels-Alder (HDA) ring-closing reaction, which is accompanied by chain compaction of the individual precursor polymer chains as determined by size exclusion chromatography (SEC). The subsequent activation step comprises a simple azidation procedure, whereas the final collapse step is driven by CuAAC in the presence of an external cross-linker, providing additional compaction to the final single-ring nanoparticles (SRNPs). The unique structure and compaction degree of the SRNPs is established via a detailed comparison with conventional single-chain nanoparticles (SCNPs) prepared exclusively by chain collapse from the exact same precursor polymer (without the prefolding step). The stepwise folding-activation-collapse approach opens new avenues for the preparation of artificial cyclotide mimetics.