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We studied the co-occurrence of microplastics (MPs) and metals in field sites and further investigated their interfacial interaction in controlled laboratory conditions. First, we detected MPs in freshwater co-occurring with metals in rural and urban areas in New Mexico. Automated particle counting and fluorescence microscopy indicated that particles in field samples ranged from 7 to 149 particles/L. The urban location contained the highest count of confirmed MPs, including polyester, cellophane, and rayon, as indicated by Attenuated Total Reflectance—Fourier Transform Infrared (ATR-FTIR) spectroscopy analyses. Metal analyses using inductively coupled plasma (ICP) revealed that bodies of water in a rural site affected by mining legacy contained up to 332.8 μg/L of U, while all bodies of water contained As concentrations below 11.4 μg/L. These field findings motivated experiments in laboratory conditions, reacting MPs with 0.02–0.2 mM of As or U solutions at acidic and neutral pH with poly(methyl-methacrylate), polyethylene, and polystyrene MPs. In these experiments, As did not interact with any of the MPs tested at pH 3 and pH 7, nor U with any MPs at pH 3. Experiments supplied with U and MPs at pH 7 indicated that MPs served as substrate surface for the adsorption and nucleation of U precipitates. Chemical speciation modeling and microscopy analyses (i.e., Transmission Electron Microscopy [TEM]) suggest that U precipitates resemble sodium-compreignacite and schoepite. These findings have relevant implications to further understanding the occurrence and interfacial interaction of MPs and metals in freshwater. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian tumors mobilize a heterogenous population of myeloid cells. While these cells initially contribute to anti-tumor immunity, as cancer progresses, they switch from immunostimulatory to immunosuppressive. Ovarian cancer is most frequently restricted to the peritoneal cavity, negating the need for systemic delivery of therapeutics. With a goal of targeting and activating myeloid cells in the tumor microenvironment, this study sought to determine which nanoparticle characteristics enhance uptake by myeloid cells in vitro and in vivo using an animal model of ovarian cancer. Lipids coating a mesoporous silica core were optimized for surface charge, formulation, and inclusion of immunogenic monophosphoryl lipid A. Benefits of a mesoporous core include opportunities for loading with additional therapeutics, such as antigens to direct immune responses or other therapeutic payloads that facilitate anti-cancer immune responses. Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins. Here, we show that an endothelial lung-homing peptide (CGSPGWVRC) interacts with C16-ceramide, a bioactive sphingolipid that mediates several biological functions. Upon binding to cell surfaces, CGSPGWVRC triggers ceramide-rich platform formation, activates acid sphingomyelinase and ceramide production, without the associated downstream apoptotic signaling. We also show that the lung selectivity of CGSPGWVRC homing peptide is dependent on ceramide production in vivo. Finally, we demonstrate two potential applications for this lipid vascular targeting system: i) as a bioinorganic hydrogel for pulmonary imaging and ii) as a ligand-directed lung immunization tool against COVID-19. Thus, C16-ceramide is a unique example of a lipid-based receptor system in the lung vascular endothelium targeted in vivo by circulating ligands such as CGSPGWVRC. [ABSTRACT FROM AUTHOR]

Emerging and re-emerging viral pathogens present a unique challenge for anti-viral therapeutic development. Anti-viral approaches with high flexibility and rapid production times are essential for combating these high-pandemic risk viruses. CRISPR-Cas technologies have been extensively repurposed to treat a variety of diseases, with recent work expanding into potential applications against viral infections. However, delivery still presents a major challenge for these technologies. Lipid-coated mesoporous silica nanoparticles (LCMSNs) offer an attractive delivery vehicle for a variety of cargos due to their high biocompatibility, tractable synthesis, and amenability to chemical functionalization. Here, we report the use of LCMSNs to deliver CRISPR-Cas9 ribonucleoproteins (RNPs) that target the Niemann–Pick disease type C1 gene, an essential host factor required for entry of the high-pandemic risk pathogen Ebola virus, demonstrating an efficient reduction in viral infection. We further highlight successful in vivo delivery of the RNP-LCMSN platform to the mouse liver via systemic administration. [ABSTRACT FROM AUTHOR]

Impaired autophagy, a cellular digestion process that eliminates proteins and damaged organelles, has been implicated in neurodegenerative diseases, including motor neuron disorders. Motor neuron targeted upregulation of autophagy may serve as a promising therapeutic approach. Lanthionine ketenamine (LK), an amino acid metabolite found in mammalian brain tissue, activates autophagy in neuronal cell lines. We hypothesized that analogs of LK can be targeted to motor neurons using nanoparticles to improve autophagy flux. Using a mouse motor neuron-like hybrid cell line (NSC-34), we tested the effect of three different LK analogs on autophagy modulation, either alone or loaded in nanoparticles. For fluorescence visualization of autophagy flux, we used a mCherry-GFP-LC3 plasmid reporter. We also evaluated protein expression changes in LC3-II/LC3-I ratio obtained by western blot, as well as presence of autophagic vacuoles per cell obtained by electron microscopy. Delivering LK analogs with targeted nanoparticles significantly enhanced autophagy flux in differentiated motor neuron-like cells compared to LK analogs alone, suggesting the need of a delivery vehicle to enhance their efficacy. In conclusion, LK analogs loaded in nanoparticles targeting motor neurons constitute a promising treatment option to induce autophagy flux, which may serve to mitigate motor neuron degeneration/loss and preserve motor function in motor neuron disease. [ABSTRACT FROM AUTHOR]

Bio/artificial hybrid nanosystems based on biological matter and synthetic nanoparticles (NPs) remain a holy grail of materials science. Herein, inspired by the well‐defined metal–organic framework (MOF) with diverse chemical diversities, the concept of "armored red blood cells" (armored RBCs) is introduced, which are native RBCs assembled within and protected by a functional exoskeleton of interlinked MOF NPs. Exoskeletons are generated within seconds through MOF NP interlocking based on metal‐phenolic coordination and RBC membrane/NP complexation via hydrogen‐bonding interactions at the cellular interface. Armored RBC formation is shown to be generalizable to many classes of MOF NPs or any NPs that can be coated by MOF. Moreover, it is found that armored RBCs preserve the original properties of RBCs (such as oxygen carrier capability and good ex ovo/in vivo circulation property) and show enhanced resistance against external stressors (like osmotic pressure, detergent, toxic NPs, and freezing conditions). By modifying the physicochemical properties of MOF NPs, armored RBCs provide the capability for blood nitric oxide sensing or multimodal imaging. The synthesis of armored RBCs is straightforward, reliable, and reversible and hence, represent a new class of hybrid biomaterials with a broad range of functionalities. [ABSTRACT FROM AUTHOR]

Porous silica-based materials have burgeoning applications ranging from fillers and additives, to adsorbents, catalysts, and recently therapeutic agents and vaccines in nanomedicine. The preponderance of these materials is made by sol-gel processing wherein soluble silica precursors are reacted to form amorphous networks composed of siloxane bonds. The facile sol-gel approach allows for an unlimited variety of binary tertiary and more complex chemical compositions including organic ligands and networks resulting in so-called organic-inorganic hybrid materials. Here, a brief review of the recent progress in sol-gel-derived silica materials prepared as particles, thin films, biosilica/silica bioreplicas (of molecules, cells and organisms), and their related preparation, properties, and bioapplications is provided. First, it highlights the recent achievements of mesoporous silica nanoparticles in biomedical applications, including therapeutic agent delivery, multimodal imaging and theranostics, and bone tissue engineering and repair. Second, the research in evaporation-induced self-assembly (EISA)-based mesostructured silica thin films and cell-directed EISA in bio/nano interfaces for various bioapplications, such as bioactive coatings, biosensing, and living cell immobilization, has been reviewed. Third, the pioneering work in biomimetic silicification/ immobilization of biomolecules and bio-organisms and silica bioreplication of complex bio-organisms is summarized. Finally, it is concluded with personal perspectives on the directions of future work on this field. [ABSTRACT FROM AUTHOR]

Porous silica‐based materials have burgeoning applications ranging from fillers and additives, to adsorbents, catalysts, and recently therapeutic agents and vaccines in nanomedicine. The preponderance of these materials is made by sol–gel processing wherein soluble silica precursors are reacted to form amorphous networks composed of siloxane bonds. The facile sol–gel approach allows for an unlimited variety of binary tertiary and more complex chemical compositions including organic ligands and networks resulting in so‐called organic–inorganic hybrid materials. Here, a brief review of the recent progress in sol–gel‐derived silica materials prepared as particles, thin films, biosilica/silica bioreplicas (of molecules, cells and organisms), and their related preparation, properties, and bioapplications is provided. First, it highlights the recent achievements of mesoporous silica nanoparticles in biomedical applications, including therapeutic agent delivery, multimodal imaging and theranostics, and bone tissue engineering and repair. Second, the research in evaporation‐induced self‐assembly (EISA)‐based mesostructured silica thin films and cell‐directed EISA in bio/nano interfaces for various bioapplications, such as bioactive coatings, biosensing, and living cell immobilization, has been reviewed. Third, the pioneering work in biomimetic silicification/immobilization of biomolecules and bio‐organisms and silica bioreplication of complex bio‐organisms is summarized. Finally, it is concluded with personal perspectives on the directions of future work on this field.The most recent progress in sol–gel‐derived silica materials prepared as particles, thin films, biosilica, and silica bioreplicas (of molecules, cells, and organisms) is reviewed. This includes their related preparation, properties, and potential biological and biomedical applications. [ABSTRACT FROM AUTHOR]

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug‐loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size‐dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non‐invasive in vivo imaging modalities. This allows for visualization and quantification of the whole‐body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non‐invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state‐of‐the‐art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseDiagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology [ABSTRACT FROM AUTHOR]

Lipid-coated mesoporous silica nanoparticles (LC-MSNs) have recently emerged as a next-generation cargo delivery nanosystem combining the unique attributes of both the organic and inorganic components. The high surface area biodegradable inorganic mesoporous silica core can accommodate multiple classes of bio-relevant cargos in large amounts, while the supported lipid bilayer coating retains the cargo and increases the stability of the nanocarrier in bio-relevant media which should promote greater bio-accumulation of LC-MSNs in cancer sites. In this contribution, we report on the optimization of various sol-gel synthesis (pH, stirring speed) and post-synthesis (hydrothermal treatment) procedures to enlarge the MSN pore size and tune the surface chemistry so as to enable loading and delivery of large biomolecules. The proof of concept of the dual cargo-loaded nanocarrier has been demonstrated in immortalized cervical cancer HeLa cells using MSNs of various fine-tuned pore sizes. Lipid-coated mesoporous silica nanoparticles were prepared for dual cargo delivery to cancer cells.The pore and particle sizes, surface areas, and condensation degrees were tuned by sol-gel processes.Sol-gel (pH, stirring speed) and post-synthesis (hydrothermal treatment) parameters were optimized. [ABSTRACT FROM AUTHOR]

Venezuelan equine encephalitis virus (VEEV) poses a major public health risk due to its amenability for use as a bioterrorism agent and its severe health consequences in humans. ML336 is a recently developed chemical inhibitor of VEEV, shown to effectively reduce VEEV infection in vitro and in vivo. However, its limited solubility and stability could hinder its clinical translation. To overcome these limitations, lipid-coated mesoporous silica nanoparticles (LC-MSNs) were employed. The large surface area of the MSN core promotes hydrophobic drug loading while the liposome coating retains the drug and enables enhanced circulation time and biocompatibility, providing an ideal ML336 delivery platform. LC-MSNs loaded 20 ± 3.4 μg ML336/mg LC-MSN and released 6.6 ± 1.3 μg/mg ML336 over 24 hours. ML336-loaded LC-MSNs significantly inhibited VEEV in vitro in a dose-dependent manner as compared to unloaded LC-MSNs controls. Moreover, cell-based studies suggested that additional release of ML336 occurs after endocytosis. In vivo safety studies were conducted in mice, and LC-MSNs were not toxic when dosed at 0.11 g LC-MSNs/kg/day for four days. ML336-loaded LC-MSNs showed significant reduction of brain viral titer in VEEV infected mice compared to PBS controls. Overall, these results highlight the utility of LC-MSNs as drug delivery vehicles to treat VEEV. [ABSTRACT FROM AUTHOR]

Bis(clickable) mesoporous silica nanospheres (ca. 100 nm) were obtained by the co-condensation of TEOS with variable amounts (2-5 % each) of two clickable organosilanes in the presence of CTAB. Such nanoparticles could be easily functionalized with two independent functions using the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction to transform them into nanomachines bearing cancer cell targeting ligands with the ability to deliver drugs on-demand. The active targeting was made possible after anchoring folic acid by CuAAC click reaction, whereas the controlled delivery was performed by clicked azobenzene fragments. Indeed, the azobenzene groups are able to obstruct the pores of the nanoparticles in the dark whereas upon irradiation in the UV or in the blue range, their trans-to- cis photoisomerization provokes disorder in the pores, enabling the delivery of the cargo molecules. The on-command delivery was proven in solution by dye release experiments, and in vitro by doxorubicin delivery. The added value of the folic acid ligand was clearly evidenced by the difference of cell killing induced by doxorubicin-loaded nanoparticles under blue irradiation, depending on whether the particles featured the clicked folic acid ligand or not. [ABSTRACT FROM AUTHOR]

New organosilica precursors containing two triethoxysilyl groups suitable for the organosilica material formation through the sol-gel process were designed and synthesised. These precursors display alkyne or azide groups for attaching targeted functional groups by copper-catalysed azide-alkyne cycloaddition (CuAAC) and can be used for the preparation of functional organosilicas following two strategies: 1) the functional group is first appended by CuAAC under anhydrous conditions, then the functional material is prepared by the sol-gel process; 2) the precursor is first subjected to the sol-gel process, producing porous, clickable bridged silsesquioxanes or periodic mesoporous organosilicas (PMOs), then the desired functional groups are attached by means of CuAAC. Herein, we show the feasibility of both approaches. A series of bridged bis(triethoxysilane)s with different pending organic moieties was prepared, demonstrating the compatibility of the first approach with many functional groups. In particular, we demonstrate that organic functional molecules bearing only one derivatisation site can be used to produce bridged organosilanes and bridged silsesquioxanes. In the second approach, clickable PMOs and porous bridged silsesquioxanes were prepared from the alkyne- or azide-containing precursors, and thereafter, functionalised with complementary model azide- or alkyne-containing molecules. These results confirmed the potential of this approach as a general methodology for preparing functional organosilicas with high loadings of functional groups. Both approaches give rise to a wide range of new functional organosilica materials. [ABSTRACT FROM AUTHOR]

The combination of the copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction with sol-gel processing enables the versatile preparation of sol-gel materials under different shapes with targeted functionalities through a diversity-oriented approach. In this account, the development of the CuAAC reaction under anhydrous conditions for the synthesis of sol-gel precursors and for the assembling of magnetic nanoparticles on self-assembled monolayers is related, as well as the use of the classical CuAAC methodologies for the functionalization of mesoporous silica nanoparticles and microdots arrays. Coupling CuAAC and Sol-Gel will result in simplified preparations of multifunctional materials with controlled morphologies. [ABSTRACT FROM AUTHOR]

This study examines intra- and intercellular trafficking of mesoporous silica nanoparticles along microtubular highways, with an emphasis on intercellular bridges connecting interphase and telophase cells. The study of nanoparticle trafficking within and between cells during all phases of the cell cycle is relevant to payload destination and dilution, and impacts delivery of therapeutic or diagnostic agents. Super-resolution stochastic optical reconstruction and sub-airy unit image acquisition, the latter combined with Huygens deconvolution microscopy, enable single nanoparticle and microtubule resolution. Combined structural and functional data provide enhanced details on biological processes, with an example of mitotic inheritance during cancer cell trivision. [ABSTRACT FROM AUTHOR]

Keywords: bioapplications; biohybrid materials; metal-organic frameworks; multifunction; red blood cells EN bioapplications biohybrid materials metal-organic frameworks multifunction red blood cells 1 1 1 03/05/21 20210303 NES 210303 In article number 2005935, Wei Zhu, Stefan Wuttke, C. Jeffrey Brinker, and co-workers assemble native red blood cells (RBCs) within and protected by functional exoskeletons of interlinked MOF nanoparticles. Red Blood Cell Superstructures: Modular Assembly of Red Blood Cell Superstructures from Metal-Organic Framework Nanoparticle-Based Building Blocks (Adv. Funct. The armored RBCs preserve the original properties of RBCs (oxygen storage) and inherit the exogenous properties of functionalizing nanoparticles. [Extracted from the article]

Simple Summary: A challenge for Nanomedicine is delivery to the site of action, most commonly the tumor microenvironment. When injected systemically, scavenger cells, such as macrophages, rapidly sequester nanoparticles. This study asks if macrophages can directly deliver scavenged nanoparticles to cancer cells via cellular connections known as tunneling nanotubes. Knowledge of the in vivo cellular fate of nanoparticles is critical for the design of optimized nanocarriers for clinical translation. Macrophages line the walls of microvasculature, extending processes into the blood flow to capture foreign invaders, including nano-scale materials. Using mesoporous silica nanoparticles (MSNs) as a model nano-scale system, we show the interplay between macrophages and MSNs from initial uptake to intercellular trafficking to neighboring cells along microtubules. The nature of cytoplasmic bridges between cells and their role in the cell-to-cell transfer of nano-scale materials is examined, as is the ability of macrophages to function as carriers of nanomaterials to cancer cells. Both direct administration of nanoparticles and adoptive transfer of nanoparticle-loaded splenocytes in mice resulted in abundant localization of nanomaterials within macrophages 24 h post-injection, predominately in the liver. While heterotypic, trans-species nanomaterial transfer from murine macrophages to human HeLa cervical cancer cells or A549 lung cancer cells was robust, transfer to syngeneic 4T1 breast cancer cells was not detected in vitro or in vivo. Cellular connections and nanomaterial transfer in vivo were rich among immune cells, facilitating coordinated immune responses. [ABSTRACT FROM AUTHOR]

The progress of nanoparticle (NP)-based drug delivery has been hindered by an inability to establish structure-activity relationships in vivo. Here, using stable, monosized, radiolabeled, mesoporous silica nanoparticles (MSNs), we apply an integrated SPECT/CT imaging and mathematical modeling approach to understand the combined effects of MSN size, surface chemistry and routes of administration on biodistribution and clearance kinetics in healthy rats. We show that increased particle size from ~32- to ~142-nm results in a monotonic decrease in systemic bioavailability, irrespective of route of administration, with corresponding accumulation in liver and spleen. Cationic MSNs with surface exposed amines (PEI) have reduced circulation, compared to MSNs of identical size and charge but with shielded amines (QA), due to rapid sequestration into liver and spleen. However, QA show greater total excretion than PEI and their size-matched neutral counterparts (TMS). Overall, we provide important predictive functional correlations to support the rational design of nanomedicines. [ABSTRACT FROM AUTHOR]