The ability to program cascades of enzymatically induced transitions of polymeric assemblies across various mesophases holds promise for developing new dynamic materials with complex response mechanisms, mimicking the intricate behavior of proteins and other biological systems. In this study, we demonstrate the feasibility of controlling the rates of such sequential transitions by molecular engineering of the polymeric building blocks. To this end, we utilized a hydrogel forming PEG-based tri-block amphiphile (TBA) and micelles forming di-block amphiphiles (DBAs), composed of dendrons with enzymatically cleavable ester end-groups as their hydrophobic blocks, to create co-assembled nano-micellar formulations. We investigated their multi-step mesophase transitions, first from micelles into macroscopic hydrogels and subsequently into water-soluble polymers, in the presence of the activating enzyme porcine liver esterase (PLE). To demonstrate the ability to control the time frame of the micelle-to-hydrogel mesophase transition, we designed and synthesized three DBAs with varying dendritic architectures and degrees of hydrophobicity. These DBAs are composed of hydrophobic dendrons with two, three, and four lipophilic end-groups, designated as DBA-C6x2, DBA-C6x3, and DBA-C6x4, respectively. Our results indicated that the co-assembled micelles containing the least hydrophobic DBA-C6x2 rapidly transformed into a hydrogel within less than two hours upon exposure to PLE. In contrast, the micellar formulation with the most hydrophobic DBA-C6x4 took over two days to transition into the hydrogel mesophase. These findings underscore the potential of using molecular engineering to tailor the behavior of programable polymeric assemblies.

Studying how synthetic polymer assemblies respond to sequential enzymatic stimuli can uncover intricate interactions in biological systems. Using amidase- and esterase-responsive PEG-based diblock (DBA) and triblock amphiphiles (TBAs), we created two distinct formulations: amidase-responsive DBA with esterase-responsive TBA and vice versa. We studied their cascade responses to the two enzymes and the sequence of their introduction. These formulations underwent cascade mesophase transitions upon the addition of the DBA-degrading enzyme, transitioning from (i) coassembled micelles to (ii) triblock-based hydrogel, and ultimately to (iii) dissolved polymers when exposed to the TBA hydrolyzing enzyme. The specific pathway of the two mesophase transitions depended on the compositions of the formulations and the enzyme introduction sequence. The results highlight the potential for designing polymeric formulations with programmable multistep enzymatic responses, mimicking the complex behavior of biological macromolecules.

In recent years, the development of nanoreactors, such as micellar nanoreactors (MNRs) for catalytic transformations, has gained significant attention due to their potential in enhancing reaction rates, selectivity, efficiency, and, as importantly, the ability to conduct organic chemistry in aqueous solutions. Among these, the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction represents a pivotal transformation and is widely used in the synthesis of bioconjugates, pharmaceuticals, and advanced materials. This study aims toward advancing our understanding of the design and utilization of polymeric amphiphiles containing tris-triazole ligands as an integral element for CuAAC reactions within MNRs. Specifically, our investigation delves into three critical factors that influence the reaction rate within MNRs: hydrophobicity, architectural configuration of the polymeric ligands, and their concentration. Utilizing the high molecular precision of dendritic amphiphiles, we synthesized polymeric ligands with two distinct architectures, namely, PEG-ditris-triazole amphiphile (DTA) and PEG-monotris-triazole amphiphile (MTA), and explored their CuAAC reactivity through coassembly with commercially available Pluronic P123 amphiphiles. The results indicate that the architecture and the concentration of the polymeric ligands play more dominant roles in influencing the reaction rate than the hydrophobicity of the dendritic blocks. Notably, while MNRs assembled from solely DTA showed a dampened reaction rate, spiking P123 micelles with DTA yielded an MNR with significantly faster rates. Moreover, P123 MNRs spiked with the synthesized MTA demonstrated increased CuAAC reaction rates compared to those spiked with the DTA, and they even outperformed the widely used Tris(benzyltriazolylmethyl)amine ligand. These findings provide valuable insights into the design principles of polymer-based ligands for constructing reactive MNRs and other types of nanoreactors for efficient catalytic transformations.

Di- and triblock amphiphiles can form different mesophases ranging from micelles to hydrogels depending on their chemical structures, hydrophilic to hydrophobic ratios, and their ratio in the mixture. In addition, their different architectures dictate their exchange rate between the assembled and unimer states and consequently affect their responsiveness toward enzymatic degradation. Here we report the utilization of the different reactivities of di- and triblock amphiphiles, having exactly the same hydrophilic to lipophilic balance, toward enzymatic degradation as a tool for programming formulations to undergo sequential enzymatically induced transitions from (i) micelles to (ii) hydrogel and finally to (iii) dissolved polymers. We show that the rate of transition between the mesophases can be programmed by changing the ratio of the amphiphiles in the formulation, and that the hydrogels can maintain encapsulated cargo, which was loaded into the micelles. The reported results demonstrate the ability of molecular architecture to serve as a tool for programming smart formulations to adopt different structures and functions.

Self-assembled systems, like polymeric micelles, have become great facilitators for conducting organic reactions in aqueous media due to their broad potential applications in green chemistry and biomedical applications. Massive strides have been taken to improve the reaction scope of such systems, enabling them to perform bioorthogonal reactions for prodrug therapy. Considering these significant advancements, we sought to study the relationships between the architecture of the amphiphiles and the reactivity of their PdII loaded micellar nanoreactors in conducting depropargylation reactions. Towards this goal, we designed and synthesized a series of isomeric polyethylene glycol (PEG)-dendron amphiphiles with different dendritic architectures but with an identical degree of hydrophobicity and hydrophilic to lipophilic balance (HLB). We observed that the dendritic architecture, which serves as the main binding site for the PdII ions, has greater influence on the reactivity than the hydrophobicity of the dendron. These trends remained constant for two different propargyl caged substrates, validating the obtained results. Density functional theory (DFT) calculations of simplified models of the dendritic blocks revealed the different binding modes of the various dendritic architectures to PdII ions, which could explain the observed differences in the reactivity of the nanoreactors with different dendritic architectures. Our results demonstrate how tuning the internal architecture of the amphiphiles by changing the orientation of the chelating moieties can be used as a tool for controlling the reactivity of PdII loaded nanoreactors.

Fracture formation due to drying is a common process in a range of systems, from mud cracks to thin polymeric films. Design and control of the fracturing process can be used as a tool for directing the fractures into predefined paths, leading to patterning and controlled fragmentation. In this work, we report the spontaneous periodic fragmentation of polymeric microfibers upon drying. The microfibers are fabricated via electrospinning of amphiphilic triblock copolymers over a glass substrate, and throughout their drying, highly periodic and sharp transverse cracking occurs along the fiber, resulting in the production of anisotropic microparticles (MPs) with a remarkably narrow size distribution. The average length of the MPs depends on the fiber's diameter; hence, by tuning the diameter of the fibers, size control over the MPs is achieved. X-ray scattering measurements reveal the formation of a lamellar arrangement of the copolymers along the fiber, providing a molecular insight into the formation of sharp transverse fractures. Adjusting the lipophilicity of the two terminal hydrophobic dendritic blocks of the triblock copolymers allows tuning the solubility of the obtained MPs in water and the release rate of hydrophobic cargo, opening a new route for the fabrication of anisotropic MPs for controlled release applications.

Di- and tri-block amphiphiles can form different mesophases ranging from micelles to hydrogels depending on their chemical structures, hydrophilic to hydrophobic ratios, and their ratio in the mixture. In addition, their different architectures dictate their exchange rate between the assembled and unimer states, and consequently affect their responsiveness towards enzymatic degradation. Here we report the utilization of the different reactivities of di- and tri-block amphiphiles towards enzymatic degradation as a tool for programming formulations to undergo three sequential enzymatically induced transitions from: (i) micelles to (ii) hydrogel and finally to (iii) dissolved polymers. We show that the rate of transition between the mesophases can be programmed by changing the ratio of the amphiphiles in the formulation, and that the hydrogels can maintain encapsulated cargo, which was loaded into the micelles. The reported results demonstrate the ability of molecular architecture to serve as a tool for programming smart formulations to adopt different structures and functions.

Single-walled carbon nanotubes (SWCNTs), non-covalently functionalized by synthetic polymers, find widespread applications including sensing and imaging. Identifying new amphiphiles with interchangeable building blocks that can form unique coronae around the SWCNT, customized for a specific application, is thus of great interest. We present polymer-dendron hybrids, composed of hydrophobic dendrons and hydrophilic polyethylene glycol (PEG), as amphiphilic macromolecules with high degree of structural freedom, for suspending SWCNTs in aqeous solution. Based on a set of four PEG-dendrons differing in their dendritic end-groups, we show thst differences in the chemical structure of the hydrophobic end-groups control the interactions of the PEG-dendrons with the SWCNT-surface. These interactions led to differences in the intrinsic near-infrared fluorescence emission of the SWCNTs and affected the PEG-dendron susceptibility to enzymatic degradation, which was monitored by the SWCNT fluorescent signal. Our findings open new avenues for rational design of SWCNT functionalization, and optical sensing of enzymatic activity