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Herein, we report a platform to integrate customizable quantities of catechol units into polymers by reacting caffeic acid carbonic anhydride with polymers having pendant amine groups. Brush poly(ethylene glycol)-caffeamide (PEG-CAF) copolymers based on oligo(ethylene glycol)methyl ether methacrylate (OEGMA

Messenger RNA (mRNA) holds great potential as a disease-modifying treatment for a wide array of monogenic disorders. Niemann-Pick disease type C1 (NP-C1) is an ultra-rare monogenic disease that arises due to loss-of-function mutations in the NPC1 gene, resulting in the entrapment of unesterified cholesterol in the lysosomes of affected cells and a subsequent reduction in their capacity for cholesterol esterification. This causes severe damage to various organs including the brain, liver, and spleen. In this work, we describe the use of NPC1-encoded mRNA to rescue the protein insufficiency and pathogenic phenotype caused by biallelic NPC1 mutations in cultured fibroblasts derived from an NP-C1 patient. We first evaluated engineering strategies for the generation of potent mRNAs capable of eliciting high protein expression across multiple cell types. We observed that “GC3” codon optimization, coupled with N1-methylpseudouridine base modification, yielded an mRNA that was approximately a thousand-fold more potent than wildtype, unmodified mRNA in a luciferase reporter assay, and consistently superior to other mRNA variants. Our data suggest that the improved expression associated with this design strategy was due in large part to the increased secondary structure of the designed mRNAs. Both codon optimization and base modification appear to contribute to increased secondary structure. Applying these principles to the engineering of NPC1-encoded mRNA, we observed a normalization in NPC1 protein levels after mRNA treatment, as well as a rescue of the mutant phenotype. Specifically, mRNA treatment restored the cholesterol esterification capacity of patient cells to wildtype levels, and induced a significant reduction in both unesterified cholesterol levels (>57% reduction compared to Lipofectamine-treated control in a cholesterol esterification assay) and lysosome size (157 μm2 reduction compared to lipofectamine-treated control). These findings show that engineered mRNA can correct the deficit caused by NPC1 mutations. More broadly, they also serve to further validate the potential of this technology to correct diseases associated with loss-of-function mutations in genes coding for large, complex, intracellular proteins.

Metal ions are ubiquitous in nature and play significant roles in assembling functional materials in fields spanning chemistry, biology, and materials science. Metal-phenolic materials are assembled from phenolic components in the presence of metal ions through the formation of metal-organic complexes. Alkali, alkali-earth, transition, and noble metal ions as well as metalloids interacting with phenolic building blocks have been widely exploited to generate diverse hybrid materials. Despite extensive studies on the synthesis of metal-phenolic materials, a comprehensive summary of how metal ions guide the assembly of phenolic compounds is lacking. A fundamental understanding of the roles of metal ions in metal-phenolic materials engineering will facilitate the assembly of materials with specific and functional properties. In this review, we focus on the diversity and function of metal ions in metal-phenolic material engineering and emerging applications. Specifically, we discuss the range of underlying interactions, including (i) cation-π, (ii) coordination, (iii) redox, and (iv) dynamic covalent interactions, and highlight the wide range of material properties resulting from these interactions. Applications (e.g., biological, catalytic, and environmental) and perspectives of metal-phenolic materials are also highlighted.

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are “nanosugars” bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes. A single subcutaneous injection of nanocomplexes shows a rapid and efficient response to a glucose challenge in two distinct diabetic mouse models, resulting in optimal blood glucose levels (below 200 mg dL–1) for up to 13 h. The morphology of the nanocomplexes is found to be key to controlling rapid and extended glucoseregulated insulin delivery in vivo. These studies reveal that the injected nanocomplexes enabled efficient insulin release in the mouse, with optimal bioavailability, pharmacokinetics, and safety profiles. These results highlight a promising strategy for the development of a glucose-responsive insulin delivery system based on a natural and biodegradable nanosugar.

Interactions between living cells and nanoparticles have been extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness and surface charge have been regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigated the role of cellular mechanosensitive components in cell-nanoparticle interactions. We demonstrate that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, we propose targeting YAP may sensitize triple negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.

Hearing loss is the most prevalent sensory disorder affecting nearly half a billion people worldwide. Aside from devices to assist hearing, such as hearing aids and cochlear implants, a drug treatment for hearing loss has yet to be developed. The neurotrophin family of growth factors has long been established as a potential therapy, however delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We previously demonstrated that direct delivery of exogenous neurotrophin-3 (NT3) in the guinea pig cochleae via a bolus injection was rapidly cleared from the inner ear, with almost complete elimination 3 days post-treatment. Here, we explored the potential of suprapaticles (SPs) for NT3 delivery to the inner ear to achieve sustained delivery over time. SPs are porous spheroid structures comprised of smaller colloidal silica nanoparticles that provide a platform for long-term controlled release of therapeutics. This study aimed to assess the pharmacokinetics and biodistribution of SP-delivered NT3. We used a radioactive tracer (iodine 125

Thrombolytic (clot-busting) therapies with plasminogen activators (PAs) are first-line treatments against acute thrombosis and ischemic stroke. However, limitations such as narrow therapeutic windows, low success rates, and bleeding complications hinder their clinical use. Drug-loaded polyphenol-based nanoparticles (NPs) could address these shortfalls by delivering a more targeted and safer thrombolysis, coupled with advantages such as improved biocompatibility and higher stability in vivo. Herein, a template-mediated polyphenol-based supramolecular assembly strategy is used to prepare nanocarriers of thrombolytic drugs. A thrombin-dependent drug release mechanism is integrated using tannic acid (TA) to cross-link urokinase-type PA (uPA) and a thrombin-cleavable peptide on a sacrificial mesoporous silica template via noncovalent interactions. Following drug loading and template removal, the resulting NPs retain active uPA and demonstrate enhanced plasminogen activation in the presence of thrombin (1.14-fold

Dynamic nanostructured materials that can react to physical and chemical stimuli have attracted interest in the biomedical and materials science fields. Metal-phenolic networks (MPNs) represent a modular class of such materials: these networks form via coordination of phenolic molecules with metal ions and can be used for surface and particle engineering. To broaden the range of accessible MPN properties, we report the fabrication of thermoresponsive MPN capsules using Fe

Metal-phenolic networks (MPNs) are amorphous materials that can be used to engineer functional films and particles. A fundamental understanding of the heat-driven structural reorganization of MPNs can offer opportunities to rationally tune their properties (ie/i.ig/i., size, permeability, wettability, hydrophobicity) for applications such as drug delivery, sensing, and tissue engineering. Herein, we use a combination of single-molecule localization microscopy, theoretical electronic structure calculations, and all-atom molecular dynamics simulations to demonstrate that MPN plasticity is governed by both the inherent flexibility of the metal (FesupIII/sup)-phenolic coordination center and the conformational elasticity of the phenolic building blocks (tannic acid, TA) that make up the metal-organic coordination complex. Thermal treatment (heating to 150 °C) of the flexible TA/FesupIII/supnetworks induces a considerable increase in the number of aromatic π-π interactions formed among TA moieties and leads to the formation of hydrophobic domains. In the case of MPN capsules, 15 min of heating induces structural rearrangements that cause the capsules to shrink (from ∼4 to ∼3 μm), resulting in a thicker (3-fold), less porous, and higher protein (ie.g./i, bovine serum albumin) affinity MPN shell. In contrast, when a simple polyphenol such as gallic acid is complexed with FesupIII/supto form MPNs, rigid materials that are insensitive to temperature changes are obtained, and negligible structural rearrangement is observed upon heating. These findings are expected to facilitate the rational engineering of versatile TA-based MPN materials with tunable physiochemical properties for diverse applications.

The development of fluorescence labeling techniques has attracted widespread interest in various fields, including biomedical science as it can facilitate high-resolution imaging and the spatiotemporal understanding of various biological processes. We report a supramolecular fluorescence labeling strategy using luminescent metal-phenolic networks (MPNs) constructed from metal ions, phenolic ligands, and common and commercially available dyes. The rapid labeling process (

An early step of evaluating a nanomaterial’s potential for biological applications is investigating its interactions with cells and biological fluids. These experiments generate complex data, which...

We report a sono-Fenton strategy to mediate the supramolecular assembly of metal-phenolic networks (MPNs) as substrate-independent coatings using phenol and phenyl derivatives as building blocks. The assembly process is initiated from the generation of hydroxyl radicals (. OH) using high-frequency ultrasound (412 kHz), while the metal ions synergistically participate in the production of additional . OH for hydroxylation/phenolation of phenol and phenyl derivatives via the Fenton reaction and also coordinate with the phenolic compounds for film formation. The coating strategy is applicable to various phenol and phenyl derivatives and different metal ions including FeII , FeIII , CuII , and CoII . In addition, the sono-Fenton strategy allows real-time control over the assembly process by turning the high-frequency ultrasound on or off. The properties of the building blocks are maintained in the formed films. This work provides an environmentally friendly and controllable method to expand the application of phenolic coatings for surface engineering.

Interfacial modular assembly has emerged as an adaptable strategy for engineering the surface properties of substrates in biomedicine, photonics, and catalysis. Herein, we report a versatile and robust coating (pBDT-TA), self-assembled from tannic acid (TA) and a self-polymerizing aromatic dithiol (i.e., benzene-1,4-dithiol, BDT), that can be engineered on diverse substrates with a precisely tuned thickness (5-40 nm) by varying the concentration of BDT used. The pBDT-TA coating is stabilized by covalent (disulfide) bonds and supramolecular (π-π) interactions, endowing the coating with high stability in various harsh aqueous environments across ionic strength, pH, temperature (e.g., 100 mM NaCl, HCl (pH 1) or NaOH (pH 13), and water at 100 °C), as well as surfactant solution (e.g., 100 mM Triton X-100) and biological buffer (e.g., Dulbecco's phosphate-buffered saline), as validated by experiments and simulations. Moreover, the reported pBDT-TA coating enables secondary reactions on the coating for engineering hybrid adlayers (e.g., ZIF-8 shells) via phenolic-mediated adhesion, and the facile integration of aromatic fluorescent dyes (e.g., rhodamine B) via π interactions without requiring elaborate synthetic processes.

A major component of designing drug delivery systems concerns how to amplify or attenuate interactions with specific cell types. For instance, a chemotherapeutic might be functionalized with an antibody to enhance binding to cancer cells ("targeting") or functionalized with polyethylene glycol to help evade immune cell recognition ("stealth"). Even at a cellular level, optimizing the binding and uptake of a drug carrier is a complex biological design problem. Thus, it is valuable to separate how strongly a new carrier interacts with a cell from the functional efficacy of a carrier's cargo once delivered to that cell. To continue the chemotherapeutic example, "how well it binds to a cancer cell" is a separate problem from "how well it kills a cancer cell". Quantitative in vitro assays for the latter are well established and usually rely on measuring viability. However, most published research on cell-carrier interactions is qualitative or semiquantitative. Generally, these measurements rely on fluorescent labeling of the carrier and, consequently, report interactions with cells in relative or arbitrary units. However, this work can be standardized and be made absolutely quantitative with a small number of characterization experiments. Such absolute quantification is valuable, as it facilitates rational, inter- and intra-class comparisons of various drug delivery systems-nanoparticles, microparticles, viruses, antibody-drug conjugates, engineered therapeutic cells, or extracellular vesicles. Furthermore, quantification is a prerequisite for subsequent meta-analyses or in silico modeling approaches. In this article, video guides, as well as a decision tree for how to achieve in vitro quantification for carrier drug delivery systems, are presented, which take into account differences in carrier size and labeling modality. Additionally, further considerations for the quantitative assessment of advanced drug delivery systems are discussed. This is intended to serve as a valuable resource to improve rational evaluation and design for the next generation of medicine.

Solar desalination is one of the most promising strategies to address the global freshwater shortage crisis. However, the residual salt accumulated on the top surface of solar evaporators severely reduces light absorption and steam evaporation efficiency, thus impeding the further industrialization of this technology. Herein, a metal-phenolic network (MPN)-engineered three-dimensional (3D) evaporator composed of photothermal superhydrophilic/superhydrophobic sponges and side-twining hydrophilic threads for efficient desalination with directional salt crystallization and zero liquid discharge is reported. The MPN coatings afford the engineering of alternating photothermal superhydrophilic/superhydrophobic sponges with high heating efficiency and defined vapor escape channels, while the side-twining threads induce site-selective salt crystallization. The 3D evaporator exhibits a high and stable indoor desalination rate (∼2.3 kg m

Surface modification with poly(ethylene glycol) (PEGylation) is an effective strategy to improve the colloidal stability of nanoparticles (NPs) and is often used to minimize cellular uptake and clearance of NPs by the immune system. However, PEGylation can also trigger the accelerated blood clearance (ABC) phenomenon, which is known to reduce the circulation time of PEGylated NPs. Herein, we report the engineering of stealth PEG NPs that can avoid the ABC phenomenon and, when modified with hyaluronic acid (HA), show specific cancer cell targeting and drug delivery. PEG NPs cross-linked with disulfide bonds are prepared by using zeolitic imidazolate framework-8 NPs as templates. The reported templating strategy enables the simultaneous removal of the template and formation of PEG NPs under mild conditions (pH 5.5 buffer). Compared to PEGylated liposomes, PEG NPs avoid the secretion of anti-PEG antibodies and the presence of anti-PEG IgM and IgG did not significantly accelerate the blood clearance of PEG NPs, indicating the inhibition of the ABC effect for the PEG NPs. Functionalization of the PEG NPs with HA affords PEG NPs that retain their stealth properties against macrophages, target CD44-expressed cancer cells and, when loaded with the anticancer drug doxorubicin, effectively inhibit tumor growth. The innovation of this study lies in the engineering of PEG NPs that can circumvent the ABC phenomenon and that can be functionalized for the improved and targeted delivery of drugs.

Glycogen-nucleic acid constructs i.e., glycoplexes are emerging promising platforms for the alteration of gene expression and transcription. Understanding the interaction of glycoplexes with human blood components, such as serum proteins and peripheral blood mononuclear cells (PBMCs), is important to overcome immune cell activation and control biodistribution upon administration of the glycoplexes in vivo. Herein, we investigated the interactions of polyethylene glycol (PEG)ylated and non-PEGylated glycoplexes carrying siRNA molecules with PBMCs isolated from the blood of healthy donors. We found that both types of glycoplexes were non-toxic and were primarily phagocytosed by monocytes without triggering a pro-inflammatory interleukin 6 cytokine production. Furthermore, we investigated the role of the protein corona on controlling the internalization efficiency in immune cells - we found that the adsorption of serum proteins, in particular haptoglobin, alpha-1-antitrypsin and apolipoprotein A-II, onto the non-PEGylated glycoplexes, significantly reduced the uptake of the glycoplexes by PBMCs. Moreover, the non-PEGylated glycoplexes were efficient in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) knockdown in monocytic THP-1 cell line. This study provides an insight into the rational design of glycogen-based nanocarriers for the safe delivery of siRNA without eliciting unwanted immune cell activation and efficient siRNA activity upon its delivery.

Surface chemistry is a major factor that determines the wettability of materials, and devising broadly applicable coating strategies that afford tunable and selective surface properties required for next-generation materials remains a challenge. Herein, we report fluorinated metal-organic coatings that display water-wetting and oil-repelling characteristics, a wetting phenomenon different from responsive wetting induced by external stimuli. We demonstrate this selective wettability with a library of metal-organic coatings using catechol-based coordination and silanization (both fluorinated and fluorine-free), enabling sensing through interfacial reconfigurations in both gaseous and liquid environments, and establish a correlation between the coating wettability and polarity of the liquids. This selective wetting performance is substrate-independent, spontaneous, durable, and reversible and occurs over a range of polar and nonpolar liquids (60 studied). These results provide insight into advanced liquid-solid interactions and a pathway toward tuning interfacial affinities and realizing robust, selective superwettability according to the surrounding conditions.

Poly(ethylene glycol) (PEG) is widely used in particle assembly to impart biocompatibility and stealth-like properties in vivo for diverse biomedical applications. Previous studies have examined the effect of PEG molecular weight and PEG coating density on the biological fate of various particles; however, there are few studies that detail the fundamental role of PEG molecular architecture in particle engineering and bio-nano interactions. Herein, we engineered PEG particles using a mesoporous silica (MS) templating method and investigated how the PEG building block architecture impacted the physicochemical properties (e.g., surface chemistry and mechanical characteristics) of the PEG particles and subsequently modulated particle-immune cell interactions in human blood. Varying the PEG architecture from 3-arm to 4-arm, 6-arm, and 8-arm generated PEG particles with a denser, stiffer structure, with increasing elastic modulus from 1.5 to 14.9 kPa, inducing an increasing level of immune cell association (from 15% for 3-arm to 45% for 8-arm) with monocytes. In contrast, the precursor PEG particles with the template intact (MS@PEG) were stiffer and generally displayed higher levels of immune cell association but showed the opposite trend-immune cell association decreased with increasing PEG arm numbers. Proteomics analysis demonstrated that the biomolecular corona that formed on the PEG particles minimally influenced particle-immune cell interactions, whereas the MS@PEG particle-cell interactions correlated with the composition of the corona that was abundant in histidine-rich glycoproteins. Our work highlights the role of PEG architecture in the design of stealth PEG-based particles, thus providing a link between the synthetic nature of particles and their biological behavior in blood.

Supramolecular complexation is a powerful strategy for engineering materials in bulk and at interfaces. Metal-phenolic networks (MPNs), which are assembled through supramolecular complexes, have emerged as suitable candidates for surface and particle engineering owing to their diverse properties. Herein, we examine the supramolecular dynamics of MPNs during thermal transformation processes. Changes in the local supramolecular network including enlarged pores, ordered aromatic packing, and metal relocation arise from thermal treatment in air or an inert atmosphere, enabling the engineering of metal-oxide networks (MONs) and metal-carbon networks, respectively. Furthermore, by integrating photo-responsive motifs (i.e., TiO2 ) and silanization, the MONs are endowed with reversible superhydrophobic (>150°) and superhydrophilic (≈0°) properties. By highlighting the thermodynamics of MPNs and their transformation into diverse materials, this work offers a versatile pathway for advanced materials engineering.

Coordination states of metal-organic materials are known to dictate their physicochemical properties and applications in various fields. However, understanding and controlling coordination sites in metal-organic systems is challenging. Herein, we report the synthesis of site-selective coordinated metal-phenolic networks (MPNs) using flavonoids as coordination modulators. The site-selective coordination was systematically investigated experimentally and computationally using ligands with one, two, and multiple different coordination sites. Tuning the multimodal Fe coordination with catechol, carbonyl, and hydroxyl groups within the MPNs enabled the facile engineering of diverse physicochemical properties including size, selective permeability (20-2000 kDa), and pH-dependent degradability. This study expands our understanding of metal-phenolic chemistry and provides new routes for the rational design of structurally tailorable coordination-based materials.

The biomolecular corona that forms on particles upon contact with blood plays a key role in the fate and utility of nanomedicines. Recent studies have shown that precoating nanoparticles with serum proteins can improve the biocompatibility and stealth properties of nanoparticles. However, it is not fully clear how precoating influences biomolecular corona formation and downstream biological responses. Herein, we systematically examine three precoating strategies by coating bovine serum albumin (single protein), fetal bovine serum (FBS, mixed proteins without immunoglobulins), or bovine serum (mixed proteins) on three nanoparticle systems, namely supramolecular template nanoparticles, metal-phenolic network (MPN)-coated template (core-shell) nanoparticles, and MPN nanocapsules (obtained after template removal). The effect of protein precoating on biomolecular corona compositions and particle-immune cell interactions in human blood was characterized. In the absence of a pre-coating, the MPN nanocapsules displayed lower leukocyte association, which correlated to the lower amount (by 2-3 fold) of adsorbed proteins and substantially fewer immunoglobulins (more than 100 times) in the biomolecular corona relative to the template and core-shell nanoparticles. Among the three coating strategies, FBS precoating demonstrated the most significant reduction in leukocyte association (up to 97% of all three nanoparticles). A correlation analysis highlights that immunoglobulins and apolipoproteins may regulate leukocyte recognition. This study demonstrates the impact of different precoating strategies on nanoparticle-immune cell association and the role of immunoglobulins in bio-nano interactions.