3D Airway Epithelial-Fibroblast Biomimetic Microfluidic Platform to Unravel Engineered Nanoparticle-Induced Acute Stress Responses as Exposome Determinants.

Insights into how biological systems respond to high- and low-dose acute environmental stressors are a fundamental aspect of exposome research. However, studying the impact of low-level environmental exposure in conventional in vitro settings is challenging. This study employed a three-dimensional (3D) biomimetic microfluidic lung-on-chip (µLOC) platform and RNA-sequencing to examine the effects of two model anthropogenic engineered nanoparticles (NPs): zinc oxide nanoparticles (Nano-ZnO) and copier center nanoparticles (Nano-CCP). The airway epithelium exposed to these NPs exhibited dose-dependent increases in cytotoxicity and barrier dysregulation (dominance of the external exposome). Interestingly, even nontoxic and low-level exposure (10 µg/mL) of the epithelium compartment to Nano-ZnO triggered chemotaxis of lung fibroblasts toward the epithelium. An increase in α smooth muscle actin (α-SMA) expression and contractile activity was also observed in these cells, indicating a bystander-like adaptive response (dominance of internal exposome). Further bioinformatics and network analysis showed that a low-dose Nano-ZnO significantly induced a robust transcriptomic response and upregulated several hub genes associated with the development of lung fibrosis. We propose that Nano-ZnO, even at a no observable effect level (NOEL) dose according to conventional standards, can function as a potent nanostressor to disrupt airway epithelium homeostasis. This leads to a cascade of profibrotic events in a cross-tissue compartment fashion. Our findings offer new insights into the early acute events of respiratory harm associated with environmental NPs exposure, paving the way for better exposomic understanding of this emerging class of anthropogenic nanopollutants.

One-Pot Synthesis of Aminated Bimodal Mesoporous Silica Nanoparticles as Silver-Embedded Antibacterial Nanocarriers and CO2 Capture Sorbents.

Mesoporous silica nanoparticles have highly versatile structural properties that are suitable for a plethora of applications including catalysis, separation, and nanotherapeutics. We report a one-pot synthesis strategy that generates bimodal mesoporous silica nanoparticles via coassembly of a structure-directing Gemini surfactant (C16-3-16) with a tetraethoxysilane/(3-aminopropyl)triethoxysilane-derived sol additive. Synthesis temperature enables control of the nanoparticle shape, structure, and mesopore architecture. Variations of the aminosilane/alkylsilane molar ratio further enable programmable adjustments of hollow to core-shell and dense nanoparticle morphologies, bimodal pore sizes, and surface chemistries. The resulting Gemini-directed aminated mesoporous silica nanoparticles have excellent carbon dioxide adsorption capacities and antimicrobial properties against Escherichia coli. Our results provide an enhanced understanding of the structure formation of multiscale mesoporous inorganic materials that are desirable for numerous applications such as carbon sequestration, water remediation, and biomedical-related applications.

Nanoparticle-induced chemoresistance: the emerging modulatory effects of engineered nanomaterials on human intestinal cancer cell redox metabolic adaptation.

The widespread use of engineered nanomaterials (ENMs) in food products necessitates the understanding of their impact on the gastrointestinal tract (GIT). Herein, we screened several representative food-borne comparator ENMs (i.e. ZnO, SiO2 and TiO2 nanoparticles (NPs)) and report that human colon cancer cells can insidiously exploit ZnO NP-induced adaptive response to acquire resistance against several chemotherapeutic drugs. By employing a conditioning and challenge treatment regime, we demonstrate that repeated exposure to a non-toxic dose of ZnO NPs (20 µM) could dampen the efficacy of cisplatin, paclitaxel and doxorubicin by 10-50% in monolayer culture and 3D spheroids of human colon adenocarcinoma cells. Structure-activity relationship studies revealed a complex interplay between nanoparticle surface chemistry and cell type in determining the chemoresistance-inducing effect, with silica coated ZnO NPs having a negligible influence on the anticancer treatment. Mechanistically, we showed that the pro-survival paracrine signaling was potentiated and propagated by a subset of ZnO NP "stressed" (Zn2++/ROS+) cells to the surrounding "bystander" (Zn2++/ROS-) cells. Transcriptome profiling, bioinformatics analysis and siRNA gene knockdown experiments revealed the nuclear factor erythroid 2-related factor 2 (Nrf2) as the key modulator of the ZnO NP-induced drug resistance. Our findings suggest that a ROS-inducing ENM can emerge as a nano-stressor, capable of regulating the chemosensitivity of colon cancer cells.

Polyoxometalates for bifunctional applications: Catalytic dye degradation and anticancer activity.

Improving the efficiencies of organic compound degradations by catalytic materials is a challenging materials research field. In our research, we successfully synthesized cobalt-based polyoxometalates (CoV-POMs) via a simple crystallization-driven self-assembly method. The incorporation of the newly synthesized CoV-POMs into peroxymonosulphate (PMS), forming a mixture, greatly enhancing the catalytic activation for a complete degradation of dye solution. The positive synergic effect between CoV-POMs and PMS was substantiated by a relatively meager degradation of less than 10% in the system without CoV-POMs, in which CoV-POMs played a vital role to activate PMS towards free radicals generation for dye degradation. Methylene blue (MB) and rhodamine B (RB) dyes were completely decolorized under 60 min with the presence of 40 mg/L CoV-POMs and 150 mg/L PMS. The CoV-POMs/PMS system was pH dependance with a lower dye degradation efficiency at elevated pH. The effect of pH was more prominent in RB dye, in which the degradation efficiency dropped drastically from 93.3% to 41.12% with the increase in the solution pH from 7 to 11. The quenching tests suggested that sulfate radicals were the dominant active species involving in the dye degradation reaction. Besides MB and RB dyes, CoV-POMs/PMS system also showed significant activity towards the degradation of phenol red (PR) and methyl orange (MO) dyes. In the biological test, CoV-POMs exhibited non-toxic behavior towards normal cells that reduced safety concern for the large-scale wastewater treatment application. In addition, the testing divulged the anticancer property of CoV-POMs with more than 35 % of A549 lung adenocarcinoma and MDA-MB-231 breast adenocarcinoma were killed with 250 mg/L CoV-POMs. The selective lethality of CoV-POMs towards cancer cells was found to be caused by different extents of cellular apoptosis. In overall, the synthesized bifunctional CoV-POMs manifested superior activities in the examined applications, specifically dye degradation and anticancer.

Diatom-inspired 2D nitric oxide releasing anti-infective porous nanofrustules.

Two-dimensional (2D) nanomaterials (NM) have emerged as promising platforms for antibacterial applications. However, the inherent "flatness" of 2D NM often limits the loading of antimicrobial components needed for synergistic bactericidal actions. Here, inspired by the highly ornamented siliceous frustules of diatoms, we prepared 2D ultrathin (<20 nm) and rigid "nanofrustule" plates via the out-of-plane growth of cetyltrimethylammonium bromide (CTAB) directed silica mesostructures on the surfaces of 2D graphene oxide nanosheets. The nanofrustules were characterized by the presence of mesoporous channels with a pore size of 3 nm and a high specific surface area of 674 m2 g-1. S-nitrosothiol-modification on the silica surfaces enables the development of a novel anti-infective nitric oxide (NO) releasing NO-nanofrustule system. The cage-like mesoporous silica architecture enabled a controlled and sustainable release of NO from the NO-nanofrustules under physiological conditions. The NO-nanofrustules displayed broad antibacterial effects against Staphylococcus aureus and Escherichia coli with a minimum inhibitory concentration of 250 µg ml-1. Mechanistic studies revealed that the antibacterial property of NO-nanofrustules was attained via a unique "capture-and-release" mode-of-action. The first step entailed the capture of the bacteria by the NO-nanofrustules to form micro-aggregates. This was followed by the release of high levels of NO to the captured bacteria to elicit a potent anti-infective effect. In combination with the lack of cytotoxicity in human dermal cells, the 2D hybrid NO-nanofrustules may be utilized to combat wound infections in clinical settings.

Potent-By-Design: Amino Acids Mimicking Porous Nanotherapeutics with Intrinsic Anticancer Targeting Properties.

Exogenous sources of amino acids are essential nutrients to fuel cancer growth. Here, the increased demand for amino acid displayed by cancer cells is unconventionally exploited as a design principle to replete cancer cells with apoptosis inducing nanoscopic porous amino acid mimics (Nano-PAAM). A small library consisting of nine essential amino acids nanoconjugates (30 nm) are synthesized, and the in vitro anticancer activity is evaluated. Among the Nano-PAAMs, l-phenylalanine functionalized Nano-PAAM (Nano-pPAAM) has emerged as a novel nanotherapeutics with excellent intrinsic anticancer and cancer-selective properties. The therapeutic efficacy of Nano-pPAAM against a panel of human breast, gastric, and skin cancer cells could be ascribed to the specific targeting of the overexpressed human large neutral amino acid transporter SLC7A5 (LAT-1) in cancer cells, and its intracellular reactive oxygen species (ROS) inducing properties of the nanoporous core. At the mechanistic level, it is revealed that Nano-pPAAM could activate both the extrinsic and intrinsic apoptosis pathways to exert a potent "double-whammy" anticancer effect. The potential clinical utility of Nano-pPAAM is further investigated using an MDA-MB-231 xenograft in NOD scid gamma mice, where an overall suppression of tumor growth by 60% is achieved without the aid of any drugs or application of external stimuli.

Inflammation Increases Susceptibility of Human Small Airway Epithelial Cells to Pneumonic Nanotoxicity.

Exposure to inhaled anthropogenic nanomaterials (NM) with dimension <100 nm has been implicated in numerous adverse respiratory outcomes. Although studies have identified key NM physiochemical determinants of pneumonic nanotoxicity, the complex interactive and cumulative effects of NM exposure, especially in individuals with preexisting inflammatory respiratory diseases, remain unclear. Herein, the susceptibility of primary human small airway epithelial cells (SAEC) exposed to a panel of reference NM, namely, CuO, ZnO, mild steel welding fume (MSWF), and nanofractions of copier center particles (Nano-CCP), is examined in normal and tumor necrosis factor alpha (TNF-α)-induced inflamed SAEC. Compared to normal SAEC, inflamed cells display an increased susceptibility to NM-induced cytotoxicity by 15-70% due to a higher basal level of intracellular reactive oxygen species (ROS). Among the NM screened, ZnO, CuO, and Nano-CCP are observed to trigger an overcompensatory response in normal SAEC, resulting in an increased tolerance against subsequent oxidative insults. However, the inflamed SAEC fails to adapt to the NM exposure due to an impaired nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated cytoprotective response. The findings reveal that susceptibility to pulmonary nanotoxicity is highly dependent on the interplay between NM properties and inflammation of the alveolar milieu.