Nanoscale polymer discs, toroids and platelets: a survey of their syntheses and potential applications.

Polymer self-assembly has become a reliable and versatile workhorse to produce polymeric nanomaterials. With appropriate polymer design and monomer selection, polymers can assemble into shapes and morphologies beyond well-studied spherical and cylindrical micellar structures. Steadfast access to anisotropic polymer nanoparticles has meant that the fabrication and application of 2D soft matter has received increasing attention in recent years. In this review, we focus on nanoscale polymer discs, toroids, and platelets: three morphologies that are often interrelated and made from similar starting materials or common intermediates. For each morphology, we illustrate design rules, and group and discuss commonly used self-assembly strategies. We further highlight polymer compositions, fundamental principles and self-assembly conditions that enable precision in bottom-up fabrication strategies. Finally, we summarise potential applications of such nanomaterials, especially in the context of biomedical research and template chemistry and elaborate on future endeavours in this space.

Self-Assembly of Rod-Coil Bottlebrush Copolymers into Degradable Nanodiscs with a UV-Triggered Self-Immolation Process.

Polymer nanodiscs, especially with stimuli-responsive features, represent an unexplored frontier in the nanomaterial landscape. Such 2D nanomaterials are considered highly promising for advanced biomedicine applications. Herein, we designed a rod-coil copolymer architecture based on an amphiphilic, tadpole-like bottlebrush copolymer, which can directly self-assemble into core-shell nanodiscs in an aqueous environment. As the bottlebrush side chains are made of amorphous, UV-responsive poly(ethyl glyoxylate) (PEtG) chains, they can undergo rapid end-to-end self-immolation upon light irradiation. This triggered nanodisc disassembly can be used to boost small molecule release from the nanodisc core, which is further aided by a morphological change from discs to spheres.

Water-Soluble Squaramide-Functionalized Copolymers for Anion Recognition.

A series of ethylene glycol-based squaramide-containing copolymers are synthesized via a post-polymerization functionalization strategy. Conversion of polymeric amines to squaramides is found to proceed in good yields, representing a versatile method of incorporating squaramides into polymers for anion recognition. Analysis of the polymers by UV-Vis and fluorescence spectroscopy revealed that anion binding takes place similarly to that of small-molecule squaramides. The presence of a fluorescent sensing group on polymer-bound squaramides allowed for a fluorescent sensing mechanism for anions that followed a similar trend in selectivity in aqueous DMSO solution, with selectivity observed for H2 PO4 - , AcO- and SO4 2- over other common anions tested. The anion response and selectivity towards anions is similar to that of analogous small-molecule squaramides, however polymeric squaramides exhibited a greater resistance to deprotonation by more basic anions, which is attributed to the closer proximity of individual squaramides on a macromolecule. The squaramide-containing polymers exhibited good water solubility, overcoming a common problem for anion sensors which are typically not sufficiently soluble in water to function in many required applications. Despite no anion binding being observed in water, this study represents a simple and effective method of creating fully water-soluble anion receptors which may be adapted to give improved binding affinity and selectivity depending on the anion binding moiety.

A Regenerable Biosensing Platform for Bacterial Toxins.

Waterborne diarrheal diseases such as travelers' diarrhea and cholera remain a threat to public health in many countries. Rapid diagnosis of an infectious disease is critical in preventing the escalation of a disease outbreak into an epidemic. Many of the diagnostic tools for infectious diseases employed today are time-consuming and require specialized laboratory settings and trained personnel. There is hence a pressing need for fit-for-purpose point-of-care diagnostic tools with emphasis in sensitivity, specificity, portability, and low cost. We report work toward thermally reversible biosensors for detection of the carbohydrate-binding domain of the Escherichia coli heat-labile enterotoxin (LTB), a toxin produced by enterotoxigenic E. coli strains, which causes travelers' diarrhea. The biosensing platform is a hybrid of two materials, combining the optical properties of porous silicon (pSi) interferometric transducers and a thermoresponsive multivalent glycopolymer, to enable recognition of LTB. Analytical performance of our biosensors allows us to detect, using a label-free format, sub-micromolar concentrations of LTB in solution as low as 0.135 µM. Furthermore, our platform shows a temperature-mediated "catch-and-release" behavior, an exciting feature with potential for selective protein capture, multiple readouts, and regeneration of the sensor over consecutive cycles of use.

Stiffness-Dependent Intracellular Location of Cylindrical Polymer Brushes.

Cylindrical polymer brushes (CPBs) are macromolecules with nanoparticle proportions. Their modular synthesis enables tailoring of their chemical composition as well as the dialing-up of overall dimensions and physicochemical properties. In this study, two rod-like poly[(ethylene glycol) methyl ether methacrylate] (PEGMA)-based CPBs with varying stiffness but otherwise comparable features and functionality, are synthesized. Differences in particle stiffness are assessed using small angle neutron scattering (SANS). It is observed that the fate of the two CPBs within cells is distinctly different. Stiffer CPBs seem to gravitate toward the mitochondria, whereas CPBs with reduced stiffness are present in different intracellular vesicles.

Cylindrical Zwitterionic Particles via Interpolyelectrolyte Complexation on Molecular Polymer Brushes.

The fabrication of macromolecular architectures with high aspect ratio and well-defined internal and external morphologies remains a challenge. The combination of template chemistry and self-assembly concepts to construct peculiar polymer architectures via a bottom-up approach is an emerging approach. In this study, a cylindrical template-namely a core-shell molecular polymer brush-and linear diblock copolymers (DBCP) associate to produce high aspect ratio polymer particles via interpolyelectrolyte complexation. Induced, morphological changes are studied using cryogenic transmission electron and atomic force microscopy, while the complexation is further followed by isothermal titration calorimetry and ξ-potential measurements. Depending on the nature of the complexing DBCP, distinct morphological differences can be achieved. While polymers with a non-ionic block lead to internal compartmentalization, polymers featuring zwitterionic domains lead to a wrapping of the brush template.

Bisphosphonate-functionalized micelles for targeted delivery of curcumin to metastatic bone cancer.

Metastatic (secondary) bone cancer is one of the major causes of death in patients with advanced cancer. A lack of options for the targeted delivery of a desired therapeutic payload to multiple tumour modules located in the bone is still one of the foremost hurdles in the treatment/prevention of metastatic bone cancer. Curcumin has a proven anticancer potential with known challenges for application as a pharmaceutical agent. We have previously shown that micellar formulations could overcome some of these challenges and enhances its anti-cancer activity. In this study, we have developed a targeted drug delivery system using bisphosphonate (alendronate) conjugated Pluronic F127 micelles that could efficiently target, and specifically deliver curcumin to the osteolytic tumour microenvironment in the bone. Characterization of the formulation of curcumin-encapsulated alendronate-conjugated micelles demonstrated that the micelles have nanoscale size (∼27 nm) with a positive surface charge (+2.87 mV) and 4% drug loading. The alendronate-conjugated micelles showed significant bone-targeting potential. Rapid binding of the micelles to hydroxyapatite surface suggested that these nanoparticles are promising carriers for effective and targeted delivery of curcumin to osteolytic tumours in the bone.

Engineering Protective Polymer Coatings for Liver Microtissues.

Three-dimensional (3D) hepatocyte microtissues (MT), also known as spheroids, have proven to be advantageous in providing more accurate information and physiologically relevant and predictive data for liver-related in vivo tests; therefore, spheroids have increasingly been used to study hepatotoxicity, drug delivery to the liver, and tissue engineering. However, variabilities in the generation of 3D MT remain a major challenge. Methods that encapsulate and protect hepatocytes offer a promising pathway in prolonging cell survival, as well as maintaining its liver cell functions. Herein, we studied the encapsulation and resultant protective effects of hydrogen bonded, biocompatible polymer coatings for hepatocyte MT in 3D cell culture. We exposed the MT to hepatotoxic nanomaterials (NMs), such as graphene oxide (GO) and cobalt oxide (Co3O4), to assess the protective effects of poly(vinylpyrrolidone) (PVPON) and tannic acid (TA) coatings. The polymer coating allowed the MT to maintain its morphology. More significantly, it increased the viability of hepatocyte-composed MT by hampering the cellular interaction between hostile NMs and hepatocytes. Based on alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, the liver cell function was maintained throughout the coating process, including after NM treatment. The study provides a straightforward and safe methodology for maintaining the morphology as well as cellular function of hepatocyte MT in vitro.

Visible-Light-Driven MADIX Polymerisation via a Reusable, Low-Cost, and Non-Toxic Bismuth Oxide Photocatalyst.

The continuous amalgamation of photocatalysis into existing reversible deactivation radical polymerisation (RDRP) processes has initiated a rapidly propagating area of polymer research in recent years. We introduce bismuth oxide (Bi2 O3 ) as a heterogeneous photocatalyst for polymerisations, operating at room temperature with visible light. We demonstrate formidable control over degenerative chain-transfer polymerisations, such as macromolecular design by interchange of xanthate (MADIX) and reversible addition-fragmentation chain-transfer (RAFT) polymerisation. We achieved narrow molecular weight distributions and attribute the excellent temporal control of a photo-induced electron transfer (PET) process. This methodology was employed to synthesise diblock copolymers combining differently activated monomers. The Bi2 O3 catalyst system has the additional benefits of low toxicity, reusability, low-cost, and ease of removal from the reaction mixture.

Polymer Nanowires with Highly Precise Internal Morphology and Topography.

The construction of precise soft matter nanostructures in solution presents a challenge. A key focus remains on the rational design of functionalities to achieve the high morphological complexity typically found in biological systems. Advances in controlled polymerizations and self-assembly increasingly allow approaches toward complex hierarchical nanomaterials. By combining tailor-made cylindrical polymer brushes, block copolymers and interpolyelectrolyte complexation-driven self-assembly, we demonstrate a facile construction of uniformly compartmentalized and topographically structured polymeric nanowires in aqueous media. The approach offers a modular avenue in programming the internal morphology of polymer nanowires by varying the block copolymer composition and topology.

Self-Assembly of Diblock Molecular Polymer Brushes in the Spherical Confinement of Nanoemulsion Droplets.

Understanding the self-assembly behavior of polymers of various topologies is key to a reliable design of functional polymer materials. Self-assembly under confinement conditions emerges as a versatile avenue to design polymer particles with complex internal morphologies while simultaneously facilitating scale-up. However, only linear block copolymers have been studied to date, despite the increasing control over macromolecule composition and architecture available. This study extends the investigation of polymer self-assembly in confinement from regular diblock copolymers to diblock molecular polymer brushes (MPBs). Block-type MPBs with polystyrene (PS) and polylactide (PLA) compartments of different sizes are incorporated into surfactant-stabilized oil-in-water (chloroform/water) emulsions. The increasing confinement in the nanoemulsion droplets during solvent evaporation directs the MPBs to form solid nano/microparticles. Microscopy studies reveal an intricate internal particle structure, including interpenetrating networks and axially stacked lamellae of PS and PLA, depending on the PS/PLA ratio of the brushes.

Synthesis and Applications of Compartmentalised Molecular Polymer Brushes.

Polymer science is rapidly advancing towards the precise construction of synthetic macromolecules of formidable complexity. Beyond the impressive advances in control over polymer composition and uniformity enabled by the living polymerisation revolution, the introduction of compartmentalisation within polymer architectures can elevate their functionality beyond that of their constituent parts, thus offering immense potential for the production of tailor-made nanomaterials. In this Minireview, we discuss synthetic routes to complex molecular brushes with discrete chemical compartments and highlight their potential in the development of advanced materials with applications in nanofabrication, optics and functional materials.

Modulated Fragmentation of Proapoptotic Peptide Nanoparticles Regulates Cytotoxicity.

Peptides perform a diverse range of physiologically important functions. The formulation of nanoparticles directly from functional peptides would therefore offer a versatile and robust platform to produce highly functional therapeutics. Herein, we engineered proapoptotic peptide nanoparticles from mitochondria-disrupting KLAK peptides using a template-assisted approach. The nanoparticles were designed to disassemble into free native peptides via the traceless cleavage of disulfide-based cross-linkers. Furthermore, the cytotoxicity of the nanoparticles was tuned by controlling the kinetics of disulfide bond cleavage, and the rate of regeneration of the native peptide from the precursor species. In addition, a small molecule drug (i.e., doxorubicin hydrochloride) was loaded into the nanoparticles to confer synergistic cytotoxic activity, further highlighting the potential application of KLAK particles in therapeutic delivery.

Shape-Dependent Activation of Cytokine Secretion by Polymer Capsules in Human Monocyte-Derived Macrophages.

Particles with tailored geometries have received significant attention due to their specific interactions with biological systems. In this work, we examine the effect of polymer capsule shape on cytokine secretion by human monocyte-derived macrophages. Thiolated poly(methacrylic acid) (PMASH) polymer capsules with different shapes (spherical, short rod-shaped, and long rod-shaped) were prepared by layer-by-layer assembly. The effect of PMASH capsule shape on cellular uptake and cytokine secretion by macrophages differentiated from THP-1 monocytes (dTHP-1) was investigated. PMASH capsules with different shapes were internalized to a similar extent in dTHP-1 cells. However, cytokine secretion was influenced by capsule geometry: short rod-shaped PMASH capsules promoted a stronger increase in TNF-α and IL-8 secretion compared with spherical (1.7-fold in TNF-α and 2.1-fold in IL-8) and long rod-shaped (2.8-fold in TNF-α and 2.0-fold in IL-8) PMASH capsules in dTHP-1 cells (capsule-to-cell ratio of 100:1). Our results indicate that the immunological response based on the release of cytokines is influenced by the shape of the polymer capsules, which could be potentially exploited in the rational design of particle carriers for vaccine delivery.

Engineered Metal-Phenolic Capsules Show Tunable Targeted Delivery to Cancer Cells.

We engineered metal-phenolic capsules with both high targeting and low nonspecific cell binding properties. The capsules were prepared by coating phenolic-functionalized hyaluronic acid (HA) and poly(ethylene glycol) (PEG) on calcium carbonate templates, followed by cross-linking the phenolic groups with metal ions and removing the templates. The incorporation of HA significantly enhanced binding and association with a CD44 overexpressing (CD44+) cancer cell line, while the incorporation of PEG reduced nonspecific interactions with a CD44 minimal-expressing (CD44-) cell line. Moreover, high specific targeting to CD44+ cells can be balanced with low nonspecific binding to CD44- cells simply by using an optimized feed-ratio of HA and PEG to vary the content of HA and PEG incorporated into the capsules. Loading an anticancer drug (i.e., doxorubicin) into the obtained capsules resulted in significantly higher cytotoxicity to CD44+ cells but lower cytotoxicity to CD44- cells.

Metal-Phenolic Supramolecular Gelation.

Materials assembled by coordination interactions between naturally abundant polyphenols and metals are of interest for a wide range of applications, including crystallization, catalysis, and drug delivery. Such an interest has led to the development of thin films with tunable, dynamic properties, however, creating bulk materials remains a challenge. Reported here is a class of metallogels formed by direct gelation between inexpensive, naturally abundant tannic acid and group(IV) metal ions. The metallogels exhibit diverse properties, including self-healing and transparency, and can be doped with various materials by in situ co-gelation. The robustness and flexibility, combined with the ease, low cost, and scalability of the coordination-driven assembly process make these metallogels potential candidates for chemical, biomedical, and environmental applications.

Engineering low-fouling and pH-degradable capsules through the assembly of metal-phenolic networks.

Metal-phenolic coordination chemistry provides a simple and rapid way to fabricate ultrathin films. Here, we report a facile strategy for the preparation of low-fouling and pH-degradable metal-phenolic network (MPN) capsules using a synthetic polyphenol derivative, poly(ethylene glycol) (PEG)-polyphenol, as a building block. PEG-MPN capsules exhibit reduced nonspecific protein adsorption and cell association compared with tannic acid (TA)-MPN capsules. In addition, they show faster disassembly at a biologically relevant pH (5) than TA-MPN capsules (80% in 5 h vs 30% in 10 days). PEG-MPN capsules combine both the low fouling properties of PEG and the advantages of the MPN-driven assembly process (e.g., fast assembly and pH-degradability).

Surface-initiated polymerization within mesoporous silica spheres for the modular design of charge-neutral polymer particles.

We report a templating approach for the preparation of functional polymer replica particles via surface-initiated polymerization in mesoporous silica templates. Subsequent removal of the template resulted in discrete polymer particles. Furthermore, redox-responsive replica particles could be engineered to disassemble in a reducing environment. Particles, made of poly(methacryloyloxyethyl phosphorylcholine) (PMPC) or poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), exhibited very low association to human cancer cells (below 5%), which renders the reported charge-neutral polymer particles a modular and versatile class of highly functional carriers with potential applications in drug delivery.

Engineering fluorescent poly(dopamine) capsules.

The recent development of poly(dopamine) (PDA) capsules provides new opportunities for their application in biology and medicine. To advance the biomedical application of PDA capsules, strategies that enable the preparation of fluorescently labeled PDA (F-PDA) capsules are required, as this will allow evaluation of their cellular interactions using a range of fluorescence-based techniques. Herein, we report a facile approach for the fabrication of F-PDA capsules via the polymerization of dopamine (DA) on sacrificial templates in the presence of hydrogen peroxide (H2O2). F-PDA capsules with well-defined sizes are prepared by templating different organic and inorganic particles. The resulting F-PDA capsules show negligible cytotoxicity in HeLa cells after incubation for 48 h. We also demonstrate visualization of the F-PDA capsules following internalization by HeLa cells using conventional fluorescence microscopy, en route toward detailed investigations on their biological interactions.