Self-Assembly of a Metal-Phenolic Sorbent for Broad-Spectrum Metal Sequestration.

Metal contamination of water bodies from industrial effluents presents a global threat to the aquatic ecosystem. To address this challenge, metal sequestration via adsorption onto solid media has been explored extensively. However, existing sorbent systems typically involve energy-intensive syntheses and are applicable to a limited range of metals. Herein, a sorbent system derived from physically cross-linked polyphenolic networks using tannic acid and ZrIV ions has been explored for high-affinity, broad-spectrum metal sequestration. The network formation step (gelation) of the sorbent is complete within 3 min and requires no special apparatus. The key to this system design is the formation of a highly stable coordination network with an optimized metal-ligand ratio (1.2:1), affording access to a major fraction of the chelating sites in tannic acid for capturing diverse metal ions. This system is stable over a pH range of 1-9, thermally stable up to ∼200 °C, and exhibits a negative surface charge (at pH 5). The sorbent system effectively sequesters 28 metals in single- and multielement model wastes, with removal efficiencies exceeding 99%. Furthermore, it is demonstrated that this system can be processed as membrane coatings, thin films, or wet gels to capture metal ions and that both the sorbent and captured metal ions can be regenerated or directly used as composite catalysts.

Ricocheting Droplets Moving on Super-Repellent Surfaces.

Droplet bouncing on repellent solid surfaces (e.g., the lotus leaf effect) is a common phenomenon that has aroused interest in various fields. However, the scenario of a droplet bouncing off another droplet (either identical or distinct chemical composition) while moving on a solid material (i.e., ricocheting droplets, droplet billiards) is scarcely investigated, despite it having fundamental implications in applications including self-cleaning, fluid transport, and heat and mass transfer. Here, the dynamics of bouncing collisions between liquid droplets are investigated using a friction-free platform that ensures ultrahigh locomotion for a wide range of probing liquids. A general prediction on bouncing droplet-droplet contact time is elucidated and bouncing droplet-droplet collision is demonstrated to be an extreme case of droplet bouncing on surfaces. Moreover, the maximum deformation and contact time are highly dependent on the position where the collision occurs (i.e., head-on or off-center collisions), which can now be predicted using parameters (i.e., effective velocity, effective diameter) through the concept of an effective interaction region. The results have potential applications in fields ranging from microfluidics to repellent coatings.

In vivo biocompatibility and immunogenicity of metal-phenolic gelation.

In vivo forming hydrogels are of interest for diverse biomedical applications due to their ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled using metal-phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. TiIV or ZrIV) provide a versatile and robust platform for engineering such materials. However, the in situ formation and in vivo response to this new class of materials has not yet been reported. Here, we demonstrate that metal-phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. The TiIV-tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivo gelation), TiIV-tannic acid materials show a substantially improved in vitro drug release profile for the corticosteroid dexamethasone (from <1 day to >10 days). These results provide essential in vivo characterization for this new class of metal-phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug delivery and regenerative medicine.

Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

Engineering Biocoatings To Prolong Drug Release from Supraparticles.

Supraparticles (SPs) assembled from smaller colloidal nanoparticles can serve as depots of therapeutic compounds and are of interest for long-term, sustained drug release in biomedical applications. However, a key challenge to achieving temporal control of drug release from SPs is the occurrence of an initial rapid release of the loaded drug (i.e., "burst" release) that limits sustained release and potentially causes burst release-associated drug toxicity. Herein, a biocoating strategy is presented for silica-SPs (Si-SPs) to reduce the extent of burst release of the loaded model protein lysozyme. Specifically, Si-SPs were coated with a fibrin film, formed by enzymatic conversion of fibrinogen into fibrin. The fibrin-coated Si-SPs, FSi-SPs, which could be loaded with 7.9 ± 0.9 µg of lysozyme per SP, released >60% of cargo protein over a considerably longer period of time of >20 days when compared with the uncoated Si-SPs that released the same amount of the cargo protein, however, within the first 3 days. Neurotrophins that support the survival and differentiation of neurons could also be loaded at ∼7.3 µg per SP, with fibrin coating also delaying neurotrophin release (only 10% of cargo released over 21 days compared with 60% from Si-SPs). In addition, the effects of incorporating a hydrogel-based system for surgical delivery and the opportunity to control drug release kinetics were investigated-an alginate-based hydrogel scaffold was used to encapsulate FSi-SPs. The introduction of the hydrogel further extended the initial release of the encapsulated lysozyme to ∼40 days (for the same amount of cargo released). The results demonstrate the increasing versatility of the SP drug delivery platform, combining large loading capacity with sustained drug release, that is tailorable using different modes of controlled delivery approaches.

Revisiting cell-particle association in vitro: A quantitative method to compare particle performance.

Nanoengineering has the potential to revolutionize medicine by designing drug delivery systems that are both efficacious and highly selective. Determination of the affinity between cell lines and nanoparticles is thus of central importance, both to enable comparison of particles and to facilitate prediction of in vivo response. Attempts to compare particle performance can be dominated by experimental artifacts (including settling effects) or variability in experimental protocol. Instead, qualitative methods are generally used, limiting the reusability of many studies. Herein, we introduce a mathematical model-based approach to quantify the affinity between a cell-particle pairing, independent of the aforementioned confounding artifacts. The analysis presented can serve as a quantitative metric of the stealth, fouling, and targeting performance of nanoengineered particles in vitro. We validate this approach using a newly created in vitro dataset, consisting of seven different disulfide-stabilized poly(methacrylic acid) particles ranging from ~100 to 1000 nm in diameter that were incubated with three different cell lines (HeLa, THP-1, and RAW 264.7). We further expanded this dataset through the inclusion of previously published data and use it to determine which of five mathematical models best describe cell-particle association. We subsequently use this model to perform a quantitative comparison of cell-particle association for cell-particle pairings in our dataset. This analysis reveals a more complex cell-particle association relationship than a simplistic interpretation of the data, which erroneously assigns high affinity for all cell lines examined to large particles. Finally, we provide an online tool (http://bionano.xyz/estimator), which allows other researchers to easily apply this modeling approach to their experimental results.

Physical stimuli-responsive vesicles in drug delivery: Beyond liposomes and polymersomes.

Over the past few decades, a range of vesicle-based drug delivery systems have entered clinical practice and several others are in various stages of clinical translation. While most of these vesicle constructs are lipid-based (liposomes), or polymer-based (polymersomes), recently new classes of vesicles have emerged that defy easy classification. Examples include assemblies with small molecule amphiphiles, biologically derived membranes, hybrid vesicles with two or more classes of amphiphiles, or more complex hierarchical structures such as vesicles incorporating gas bubbles or nanoparticulates in the lumen or membrane. In this review, we explore these recent advances and emerging trends at the edge and just beyond the research fields of conventional liposomes and polymersomes. A focus of this review is the distinct behaviors observed for these classes of vesicles when exposed to physical stimuli - such as ultrasound, heat, light and mechanical triggers - and we discuss the resulting potential for new types of drug delivery, with a special emphasis on current challenges and opportunities.

Coatings super-repellent to ultralow surface tension liquids.

High-performance coatings that durably and fully repel liquids are of interest for fundamental research and practical applications. Such coatings should allow for droplet beading, roll off and bouncing, which is difficult to achieve for ultralow surface tension liquids. Here we report a bottom-up approach to prepare super-repellent coatings using a mixture of fluorosilanes and cyanoacrylate. On application to surfaces, the coatings assemble into thin films of locally multi-re-entrant hierarchical structures with very low surface energies. The resulting materials are super-repellent to solvents, acids and bases, polymer solutions and ultralow surface tension liquids, characterized by ultrahigh liquid contact angles (>150°) and negligible roll-off angles (~0°). Furthermore, the coatings are transparent, durable and demonstrate universal liquid bouncing, tailored responsiveness and anti-freezing properties, and are thus a promising alternative to existing synthetic super-repellent coatings.

Minimum information reporting in bio-nano experimental literature.

Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our fundamental understanding of the bio-nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a 'minimum information standard' for experimental literature investigating bio-nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio-nano materials, and facilitate meta analyses and in silico modelling.

Gel-Mediated Electrospray Assembly of Silica Supraparticles for Sustained Drug Delivery.

Supraparticles (SPs) composed of smaller colloidal particles provide a platform for the long-term, controlled release of therapeutics in biomedical applications. However, current synthesis methods used to achieve high drug loading and those involving biocompatible materials are often tedious and low throughput, thereby limiting the translation of SPs to diverse applications. Herein, we present a simple, effective, and automatable alginate-mediated electrospray technique for the assembly of robust spherical silica SPs (Si-SPs) for long-term (>4 months) drug delivery. The Si-SPs are composed of either porous or nonporous primary Si particles within a decomposable alginate matrix. The size and shape of the Si-SPs can be tailored by controlling the concentrations of alginate and silica primary particles used and key electrospraying parameters, such as flow rate, voltage, and collector distance. Furthermore, the performance (including drug loading kinetics, loading capacity, loading efficiency, and drug release) of the Si-SPs can be tuned by changing the porosity of the primary particles and through the retention or removal (via calcination) of the alginate matrix. The structure and morphology of the Si-SPs were characterized by electron microscopy, dynamic light scattering, N2 adsorption-desorption analysis, and X-ray photoelectron spectroscopy. The cytotoxicity and degradability of the Si-SPs were also examined. Drug loading kinetics and loading capacity for six different types of Si-SPs, using a model protein drug (fluorescently labeled lysozyme), demonstrate that Si-SPs prepared from primary silica particles with large pores can load significant amounts of lysozyme (∼10 µg per SP) and exhibit sustained, long-term release of more than 150 days. Our experiments show that Si-SPs can be produced through a gel-mediated electrospray technique that is robust and automatable (important for clinical translation and commercialization) and that they present a promising platform for long-term drug delivery.

Nanoengineering of Poly(ethylene glycol) Particles for Stealth and Targeting.

The assembly of particles composed solely or mainly of poly(ethylene glycol) (PEG) is an emerging area that is gaining increasing interest within bio-nano science. PEG, widely considered to be the "gold standard" among polymers for drug delivery, is providing a platform for exploring fundamental questions and phenomena at the interface between particle engineering and biomedicine. These include the targeting and stealth behaviors of synthetic nanomaterials in biological environments. In this feature article, we discuss recent work in the nanoengineering of PEG particles and explore how they are enabling improved targeting and stealth performance. Specific examples include PEG particles prepared through surface-initiated polymerization, mesoporous silica replication via postinfiltration, and particle assembly through metal-phenolic coordination. This particle class exhibits unique in vivo behavior (e.g., biodistribution and immune cell interactions) and has recently been explored for drug delivery applications.

Overcoming the Blood-Brain Barrier: The Role of Nanomaterials in Treating Neurological Diseases.

Therapies directed toward the central nervous system remain difficult to translate into improved clinical outcomes. This is largely due to the blood-brain barrier (BBB), arguably the most tightly regulated interface in the human body, which routinely excludes most therapeutics. Advances in the engineering of nanomaterials and their application in biomedicine (i.e., nanomedicine) are enabling new strategies that have the potential to help improve our understanding and treatment of neurological diseases. Herein, the various mechanisms by which therapeutics can be delivered to the brain are examined and key challenges facing translation of this research from benchtop to bedside are highlighted. Following a contextual overview of the BBB anatomy and physiology in both healthy and diseased states, relevant therapeutic strategies for bypassing and crossing the BBB are discussed. The focus here is especially on nanomaterial-based drug delivery systems and the potential of these to overcome the biological challenges imposed by the BBB. Finally, disease-targeting strategies and clearance mechanisms are explored. The objective is to provide the diverse range of researchers active in the field (e.g., material scientists, chemists, engineers, neuroscientists, and clinicians) with an easily accessible guide to the key opportunities and challenges currently facing the nanomaterial-mediated treatment of neurological diseases.

Supramolecular Metal-Phenolic Gels for the Crystallization of Active Pharmaceutical Ingredients.

The use of supramolecular gel media for the crystallization of active pharmaceutical ingredients (APIs) is of interest for controlling crystal size, morphology, and polymorphism, as these features determine the performance of pharmaceutical formulations. In contrast to supramolecular systems prepared from synthetic gelators, herein, supramolecular metallogels based on a natural polyphenol (tannic acid) are used for the crystallization of APIs. The gel-grown API crystals exhibit considerable differences in size, morphology, and polymorphism when compared with those formed in solutions. These physical features can also be tailored by varying the gel composition and additives, suggesting an influence of the gel medium on the crystallization outcomes. Furthermore, these gel-API crystal composites can be used for sustained drug release, indicating their potential as drug delivery systems. The facile preparation of these supramolecular gels and the use of naturally abundant components in their synthesis provide a generic platform for studying gel-mediated crystallization of diverse APIs.

Particle Targeting in Complex Biological Media.

Over the past few decades, nanoengineered particles have gained increasing interest for applications in the biomedical realm, including diagnosis, imaging, and therapy. When functionalized with targeting ligands, these particles have the potential to interact with specific cells and tissues, and accumulate at desired target sites, reducing side effects and improve overall efficacy in applications such as vaccination and drug delivery. However, when targeted particles enter a complex biological environment, the adsorption of biomolecules and the formation of a surface coating (e.g., a protein corona) changes the properties of the carriers and can render their behavior unpredictable. For this reason, it is of importance to consider the potential challenges imposed by the biological environment at the early stages of particle design. This review describes parameters that affect the targeting ability of particulate drug carriers, with an emphasis on the effect of the protein corona. We highlight strategies for exploiting the protein corona to improve the targeting ability of particles. Finally, we provide suggestions for complementing current in vitro assays used for the evaluation of targeting and carrier efficacy with new and emerging techniques (e.g., 3D models and flow-based technologies) to advance fundamental understanding in bio-nano science and to accelerate the development of targeted particles for biomedical applications.

Multiligand Metal-Phenolic Assembly from Green Tea Infusions.

The synthesis of hybrid functional materials using the coordination-driven assembly of metal-phenolic networks (MPNs) is of interest in diverse areas of materials science. To date, MPN assembly has been explored as monoligand systems (i.e., containing a single type of phenolic ligand) where the phenolic components are primarily obtained from natural sources via extraction, isolation, and purification processes. Herein, we demonstrate the fabrication of MPNs from a readily available, crude phenolic source-green tea (GT) infusions. We employ our recently introduced rust-mediated continuous assembly strategy to prepare these GT MPN systems. The resulting hollow MPN capsules contain multiple phenolic ligands and have a shell thickness that can be controlled through the reaction time. These multiligand MPN systems have different properties compared to the analogous MPN systems reported previously. For example, the Young's modulus (as determined using colloidal-probe atomic force microscopy) of the GT MPN system presented herein is less than half that of MPN systems prepared using tannic acid and iron salt solutions, and the disassembly kinetics are faster (∼50%) than other, comparable MPN systems under identical disassembly conditions. Additionally, the use of rust-mediated assembly enables the formation of stable capsules under conditions where the conventional approach (i.e., using iron salt solutions) results in colloidally unstable dispersions. These differences highlight how the choice of phenolic ligand and its source, as well as the assembly protocol (e.g., using solution-based or solid-state iron sources), can be used to tune the properties of MPNs. The strategy presented herein expands the toolbox of MPN assembly while also providing new insights into the nature and robustness of metal-phenolic interfacial assembly when using solution-based or solid-state metal sources.

Robust Chemistry: The Importance of Data and Methods Sharing.

"… Robustness in chemistry can be enhanced by increasing the adoption of best data-sharing practices and the use of photos and videos for sharing methods and practical knowledge. Journals are an integral part of the foundation of scientific endeavor, and methods and data sharing are complementary practices that could lead to a step change in how we conduct and report research …" Read more in the Editorial by Mattias Björnmalm and Frank Caruso.

Bridging Bio-Nano Science and Cancer Nanomedicine.

The interface of bio-nano science and cancer medicine is an area experiencing much progress but also beset with controversy. Core concepts of the field-e.g., the enhanced permeability and retention (EPR) effect, tumor targeting and accumulation, and even the purpose of "nano" in cancer medicine-are hotly debated. In parallel, considerable advances in neighboring fields are occurring rapidly, including the recent progress of "immuno-oncology" and the fundamental impact it is having on our understanding and the clinical treatment of the group of diseases collectively known as cancer. Herein, we (i) revisit how cancer is commonly treated in the clinic and how this relates to nanomedicine; (ii) examine the ongoing debate on the relevance of the EPR effect and tumor targeting; (iii) highlight ways to improve the next-generation of nanomedicines; and (iv) discuss the emerging concept of working with (and not against) biology. While discussing these controversies, challenges, emerging concepts, and opportunities, we explore new directions for the field of cancer nanomedicine.

Rust-Mediated Continuous Assembly of Metal-Phenolic Networks.

The use of natural compounds for preparing hybrid molecular films-such as surface coatings made from metal-phenolic networks (MPNs)-is of interest in areas ranging from catalysis and separations to biomedicine. However, to date, the film growth of MPNs has been observed to proceed in discrete steps (≈10 nm per step) where the coordination-driven interfacial assembly ceases beyond a finite time (≈1 min). Here, it is demonstrated that the assembly process for MPNs can be modulated from discrete to continuous by utilizing solid-state reactants (i.e., rusted iron objects). Gallic acid etches iron from rust and produces chelate complexes in solution that continuously assemble at the interface of solid substrates dispersed in the system. The result is stable, continuous growth of MPN films. The presented double dynamic process-that is, etching and self-assembly-provides new insights into the chemistry of MPN assembly while enabling control over the MPN film thickness by simply varying the reaction time.