This feature article reviews our recent advancements on the synthesis, phase behavior, and micellar structures of diblock copolymers consisting of oppositely thermoresponsive blocks in aqueous environments These copolymers combine a nonionic block, which shows lower critical solution temperature (LCST) behavior, with a zwitterionic block that exhibits an upper critical solution temperature (UCST) The transition temperature of the latter class of polymers is strongly controlled by its molar mass and by the salt concentration, in contrast to the rather invariant transition of nonionic polymers with type II LCST behavior such as poly(N-isopropylacrylamide) or poly(N-isopropyl methacrylamide) This allows for implementing the sequence of the UCST and LCST transitions of the polymers at will by adjusting either molecular or, alternatively, physical parameters Depending on the location of the transition temperatures of both blocks, different switching scenarios are realized from micelles to inverse micelles, namely via the molecularly dissolved state, the aggregated state, or directly In addition to studies of (semi)dilute aqueous solutions, highly concentrated systems have also been explored, namely water-swollen thin films Concerning applications, we discuss the possible use of the diblock copolymers as "smart" nanocarriers

Switch It Inside-Out: "Schizophrenic" Behavior of All Thermoresponsive UCST-LCST Diblock Copolymers.

Solubilization locations play a critical role in developing advanced surfactants and improving solubilization power in micelle-based applications. However, the current polarity-based techniques for measuring solubilization locations could come to conflicting conclusions. The key challenge is the unpredictable polarities in the micellar microenvironment. Now, an approach that is independent of micellar polarities is used to measure solubilization locations by covalently linking tetraphenylethylene (TPE) to the alkyl chain end of cationic surfactants. The solubilization locations of solubilized acceptors in the TPE-cored spherical micelles were accurately measured by calculating the Forster resonance energy transfer distance between anchored TPE donors and solubilized acceptors. Solubilization locations of solubilized substances in the micellar interior and at the micellar surface depend on their size and hydrophobicity, respectively.

Measurement of Solubilization Location in Micelles Using Anchored Aggregation-Induced Emission Donors.

https://pubs.rsc.org/en/content/articlepdf/2020/py/d0py01161d

Effects of crystallinity and dispersity on the self-assembly behavior of block co-oligomers in water

H2O2-activated in situ polymerization of aniline derivative in hydrogel for real-time monitoring and inhibition of wound bacterial infection.

Cells contain membraneless compartments that assemble due to liquid-liquid phase separation, including biomolecular condensates with complex morphologies. For instance, certain condensates are surrounded by a film of distinct composition, such as Ape1 condensates coated by a layer of Atg19, required for selective autophagy in yeast. Other condensates are multiphasic, with nested liquid phases of distinct compositions and functions, such as in the case of ribosome biogenesis in the nucleolus. The size and structure of such condensates must be regulated for proper biological function. We leveraged a bio-inspired approach to discover how amphiphilic, surfactant-like proteins may contribute to the structure and size regulation of biomolecular condensates. We designed and examined families of amphiphilic proteins comprising one phase-separating domain and one non-phase separating domain. In particular, these proteins contain the soluble structured domain glutathione S-transferase (GST) or maltose binding protein (MBP), fused to the intrinsically disordered RGG domain from P granule protein LAF-1. When one amphiphilic protein is mixed in vitro with RGG-RGG, the proteins assemble into enveloped condensates, with RGG-RGG at the core, and the amphiphilic protein forming the surface film layer. Importantly, we found that MBP-based amphiphiles are surfactants and control droplet size, with increasing surfactant concentration resulting in smaller droplet radii. In contrast, GST-based amphiphiles at increased concentrations co-assemble with RGG-RGG into multiphasic structures. We propose a mechanism for these experimental observations, supported by molecular simulations of a minimalist model. We speculate that surfactant proteins may play a significant role in regulating the structure and function of biomolecular condensates.

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Amphiphilic proteins coassemble into multiphasic condensates and act as biomolecular surfactants

Fascinating properties are displayed by synthetic multicomponent supramolecular systems that comprise a manifold of competitive interactions, thereby mimicking natural processes. We present the integration of two reentrant phase transitions based on an unexpected dilution-induced assembly process using supramolecular polymers and surfactants. The co-assembly of the water-soluble benzene-1,3,5-tricarboxamide (BTA-EG4) and a surfactant at a specific ratio yielded small-sized aggregates. These interactions were modeled using the competition between self-sorting and co-assembly of both components. The small-sized aggregates were transformed into supramolecular polymer networks by a twofold dilution in water without changing their ratio. Kinetic experiments show the in situ growth of micrometer-long fibers in the dilution process. We were able to create systems that undergo fully reversible hydrogel-solution-hydrogel-solution transitions upon dilution by introducing another orthogonal interaction. Description Dilution-induced ordering Many molecules, such as surfactants, can form ordered structures when placed in solution. Typically, the systems become more ordered and the structures change from spheres to elongated shapes as the concentration is increased. Su et al. studied a system of benzene-1,3,5-tricarboxamide) (BTA-EG4) with the cationic surfactant octyltrimethylammonium bromide (OTAB), in water (see the Perspective by Webber). BTA-EG4 undergoes supramolecular polymerization in water and will form hydrogels at higher concentrations, whereas OTAB will form small aggregates. However, when combined, the OTAB initially disrupts the BTA-EG4 hydrogels, but these can be reestablished upon dilution because this lessens the effect of the surfactant. With careful engineering, this can be expanded to a gel-sol-gel-sol system as a function of concentration. —MSL Dilution-induced gelation in multicomponent supramolecular systems leads to highly adaptive hydrogel materials.

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Dilution-induced gel-sol-gel-sol transitions by competitive supramolecular pathways in water

The solubilization of lyophobic compounds in block copolymer micelles has been extensively investigated but remains only partially understood. There is a need to understand the fundamental parameters that determine the spatial distribution of the solubilized compounds within the micelles. Controlling this feature is a key aspect in the design of drug delivery systems with tailored release properties. Using Scheutjens-Fleer self-consistent field (SF-SCF) computations, we found that solubilization is regulated by a complex interplay between enthalpic and entropic contributions and that the spatial distribution can be controlled by the concentration and solubility of the guest compound in the dispersion medium. Upon solubilization, a characteristic change in size and mass of the micelles is predicted. This can be used as a fingerprint to indirectly assess the spatial distribution. Based on these findings, we developed two experimental protocols to control and assess the spatial distribution of lyophobic compounds within block copolymer micelles.

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Controlling the spatial distribution of solubilized compounds within copolymer micelles

Precise control over the folding pathways of polypeptides using a combination of noncovalent and covalent interactions has evolved into a wide range of functional proteins with a perfectly defined 3D conformation. Inspired hereby, we develop a series of amphiphilic copolymers designed to form compact, stable, and structured single-chain polymeric nanoparticles (SCPNs) of defined size, even in competitive conditions. The SCPNs are formed through a combination of noncovalent interactions (hydrophobic and hydrogen-bonding interactions) and covalent intramolecular cross-linking using a light-induced [2 + 2] cycloaddition. By comparing different self-assembly pathways of the nanoparticles, we show that, like for proteins in nature, the order of events matters. When covalent cross-links are formed prior to the folding via hydrophobic and supramolecular interactions, larger particles with less structured interiors are formed. In contrast, when the copolymers first fold via hydrophobic and hydrogen-bonding interactions into compact conformations, followed by covalent cross-links, good control over the size of the SCPNs and microstructure of the hydrophobic interior is achieved. Such a structured SCPN can stabilize the solvatochromic dye benzene-1,3,5-tricarboxamide–Nile Red via molecular recognition for short periods of time in complex media, while showing slow exchange dynamics with the surrounding complex media at longer time scales. The SCPNs show good biocompatibility with cells and can carry cargo into the lysosomal compartments of the cells. Our study highlights the importance of control over the folding pathway in the design of stable SCPNs, which is an important step forward in their application as noncovalent drug or catalyst carriers in biological settings.

https://pubs.acs.org/doi/pdf/10.1021/acs.macromol.2c00930

En Route to Stabilized Compact Conformations of Single-Chain Polymeric Nanoparticles in Complex Media

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Simultaneously controlling conformational and operational stability of single-chain polymeric nanoparticles in complex media

The folding of proteins into functional nanoparticles with defined 3D structures has inspired chemists to create simple synthetic systems mimicking protein properties. The folding of polymers into nanoparticles in water proceeds via different strategies, resulting in the global compaction of the polymer chain. Herein, we review the different methods available to control the conformation of synthetic polymers and collapse / fold them into structured, functional nanoparticles, such as hydrophobic collapse, supramolecular self-assembly, and covalent cross-linking. A comparison is made between the design principles of protein folding to synthetic polymer folding and the formation of structured nanocompartments in water, highlighting similarities and differences in design and function. We also focus on the importance of structure for functional stability and diverse applications in complex media and cellular environments.

Stefan Wijker

Papers

Dilution-induced gel-sol-gel-sol transitions by competitive supramolecular pathways in water

Controlling the spatial distribution of solubilized compounds within copolymer micelles

En Route to Stabilized Compact Conformations of Single-Chain Polymeric Nanoparticles in Complex Media

Simultaneously controlling conformational and operational stability of single-chain polymeric nanoparticles in complex media

Protein-Inspired Control over Synthetic Polymer Folding for Structured Functional Nanoparticles in Water.