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-EG 4 ) 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.

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.

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.

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.

Single-chain polymeric nanoparticles (SCPNs) comprising a solvatochromic pyrazoline adduct show conformational and operational stability in complex media and in cellular compartments; the connectivity of the adduct is crucial in modulating...