Search

Much has been learned about the protein coronae and their biological implications within the context of nanomedicine and nanotoxicology. However, no data is available about the protein coronae associated with nanoparticles undergoing spontaneous surface-energy minimization, a common phenomenon during the synthesis and shelf life of nanomaterials. Accordingly, here we employed gold nanoparticles (AuNPs) possessing the three initial states of spiky, midspiky, and spherical shapes and determined their acquisition of human plasma protein coronae with label-free mass spectrometry. The AuNPs collected coronal proteins that were different in abundance, physicochemical parameters, and interactive biological network. The size and structure of the coronal proteins matched the morphology of the AuNPs, where small globular proteins and large fibrillar proteins were enriched on spiky AuNPs, while large proteins were abundant on spherical AuNPs. Furthermore, the AuNPs induced endothelial leakiness to different degrees, which was partially negated by their protein coronae as revealed by confocal fluorescence microscopy, in vitro and ex vivo transwell assays, and signaling pathway assays. This study has filled a knowledge void concerning the dynamic protein corona of nanoparticles possessing an evolving morphology and shed light on their implication for future nanomedicine harnessing the paracellular pathway.

Background With the continued integration of engineered nanomaterials (ENMs) into everyday applications, it is important to understand their potential for inducing adverse human health effects. However, standard in vitro hazard characterisation approaches suffer limitations for evaluating ENM and so it is imperative to determine these potential hazards under more physiologically relevant and realistic exposure scenarios in target organ systems, to minimise the necessity for in vivo testing. The aim of this study was to determine if acute (24 h) and prolonged (120 h) exposures to five ENMs (TiO2, ZnO, Ag, BaSO4 and CeO2) would have a significantly different toxicological outcome (cytotoxicity, (pro-)inflammatory and genotoxic response) upon 3D human HepG2 liver spheroids. In addition, this study evaluated whether a more realistic, prolonged fractionated and repeated ENM dosing regime induces a significantly different toxicity outcome in liver spheroids as compared to a single, bolus prolonged exposure. Results Whilst it was found that the five ENMs did not impede liver functionality (e.g. albumin and urea production), induce cytotoxicity or an IL-8 (pro-)inflammatory response, all were found to cause significant genotoxicity following acute exposure. Most statistically significant genotoxic responses were not dose-dependent, with the exception of TiO2. Interestingly, the DNA damage effects observed following acute exposures, were not mirrored in the prolonged exposures, where only 0.2–5.0 µg/mL of ZnO ENMs were found to elicit significant (p ≤ 0.05) genotoxicity. When fractionated, repeated exposure regimes were performed with the test ENMs, no significant (p ≥ 0.05) difference was observed when compared to the single, bolus exposure regime. There was Conclusion In conclusion, whilst there was no difference between a single, bolus or fractionated, repeated ENM prolonged exposure regimes upon the toxicological output of 3D HepG2 liver spheroids, there was a difference between acute and prolonged exposures. This study highlights the importance of evaluating more realistic ENM exposures, thereby providing a future in vitro approach to better support ENM hazard assessment in a routine and easily accessible manner.

Although nanotoxicology studies have shown that respiratory exposure of titanium dioxide nanoparticles (TiO2 NPs) could induce adverse health effects, limited biomarkers associated with occupational exposure of TiO2 NPs were reported. The purpose of this study is to screen serum biomarkers among workers occupationally exposed to TiO2 NPs using metabolomics. Compared with the control group, a total of 296 serum metabolites were differentially expressed in the TiO2 NPs-exposed group, of which the relative expression of 265 metabolites increased, and the remaining 31 decreased. Three machine learning methods including random forest (RF), support vector machines (SVM), and boruta screened eight potential biomarkers and simultaneously selected a metabolite, Liquoric acid. Through multiple linear regression analysis to adjust the influence of confounding factors such as gender, age, BMI, smoking and drinking, occupational exposure to TiO2 NPs was significantly related to the relative expression of the eight potential biomarkers. Meanwhile, the receiver operating characteristic curves (ROCs) of these potential biomarkers had good sensitivity and specificity. These potential biomarkers were related to lipid peroxidation, and had biological basis for occupational exposure to TiO2 NPs. Therefore, it was demonstrated that the serum metabolites represented by Liquoric acid were good biomarkers of occupational exposure to TiO2 NPs.

The titanium dioxide nanoparticles (NPs) have been applied to biomedical, pharmaceutical, and food additive fields. However, the effect on health and the environment are conflicting; thus, it has been reviewing several times. In this context, establishing standard robust protocols for detecting cytotoxicity and genotoxicity of nanomaterials became essential for nanotechnology development. The cell type and the intrinsic characteristics of titanium dioxide NPs can influence nanotoxicity. In this work, the cyto- and genotoxicity effects of standard reference material titanium dioxide NPs in primary bovine fibroblasts and immortalized Chinese hamster ovary epithelial (CHO) cells were determined and compared for the first time. Titanium dioxide NPs exposure revealed no cytotoxicity for primary bovine fibroblasts, while only higher concentrations tested (10 μg/ml) induce genotoxic effects in this cell model. In contrast, the lower concentrations of the titanium dioxide NPs cause the cyto- and genotoxic effects in CHO cells. Therefore, our finding indicates that the CHO line was more sensitive toward the effects of titanium dioxide NPs than the primary bovine fibroblast, which should be valuable for their environmental risk assessment.

Nanotoxicology is argued and considered one of the emerging topics. In this study, polyaniline (PANI)/2-acrylamido-2-methylpropanesulfonic acid (AMPSA) capped silver nanoparticles (NPs)/graphene oxide (GO) quantum dots (QDs) nanocomposite (PANI/Ag (AMPSA)/GO QDs NC) as a nanoadsorbent has a potential for removal of toxic hexavalent chromium (Cr(VI)) ions from water. The acute toxicity of this NC was evaluated on Artemia salina and freshwater Ostracods (Cypridopsis vidua) larvae for 48 h. The measurements were made at 24 and 48 h with 3 repetitions. The 50% effective concentration (EC50) values of the NC were determined after the exposure of these organisms. According to the results of the optical microscope, it was found that both experimental organisms intake the NC. In the toxicity results of Ostracods, the NC had a highly toxic effect only at 250 mg/L after 48 h and the EC50 value was 157.6 ± 6.4 mg/L. For Artemia salina individuals, it was noted that they were less sensitive than the Ostracods and EC50 value was 476 ± 25.1 mg/L after 48 h. These results indicated that PANI/Ag (AMPSA)/GO QDs NC has low toxicity towards both investigated organisms.

The unique properties of carbon nanotubes (CNTs) (such as their high surface to volume ratios, enhanced conductivity and strength, biocompatibility, ease of functionalization, optical properties, etc.) have led to their consideration to serve as novel drug and gene delivery carriers. CNTs are effectively taken up by many different cell types through several mechanisms. CNTs have acted as carriers of anticancer molecules (including docetaxel (DTX), doxorubicin (DOX), methotrexate (MTX), paclitaxel (PTX), and gemcitabine (GEM)), anti-inflammatory drugs, osteogenic dexamethasone (DEX) steroids, etc. In addition, the unique optical properties of CNTs have led to their use in a number of platforms for improved photo-therapy. Further, the easy surface functionalization of CNTs has prompted their use to deliver different genes, such as plasmid DNA (PDNA), micro-RNA (miRNA), and small interfering RNA (siRNA) as gene delivery vectors for various diseases such as cancers. However, despite all of these promises, the most important continuous concerns raised by scientists reside in CNT nanotoxicology and the environmental effects of CNTs, mostly because of their non-biodegradable state. Despite a lack of widespread FDA approval, CNTs have been studied for decades and plenty of in vivo and in vitro reports have been published, which are reviewed here. Lastly, this review covers the future research necessary for the field of CNT medicine to grow even further.

Many nanoscale biomaterials fail to reach the clinical trial stage due to a poor understanding of the fundamental principles of their in vivo behaviour. Here we describe the transport, transformation and bioavailability of MoS2 nanomaterials through a combination of in vivo experiments and molecular dynamics simulations. We show that after intravenous injection molybdenum is significantly enriched in liver sinusoid and splenic red pulp. This biodistribution is mediated by protein coronas that spontaneously form in the blood, principally with apolipoprotein E. The biotransformation of MoS2 leads to incorporation of molybdenum into molybdenum enzymes, which increases their specific activities in the liver, affecting its metabolism. Our findings reveal that nanomaterials undergo a protein corona-bridged transport–transformation–bioavailability chain in vivo, and suggest that nanomaterials consisting of essential trace elements may be converted into active biological molecules that organisms can exploit. Our results also indicate that the long-term biotransformation of nanomaterials may have an impact on liver metabolism. Understanding the in vivo biotransformation of nanomaterials used for biomedical applications might shed light on their long-term effects and safety. Here the authors show that molybdenum derived from nanomaterials is mainly transported in the liver, in a corona-mediated process, and is incorporated in molybdoenzymes, with an effect on liver metabolism.

Iron oxide nanoparticles gain increasing attention due to their broad industrial use. However, safety concerns exist since their effects on human cells are still under investigation. The presence of iron oxide nanoparticles in the food pigment E172 has been shown recently. Here, we studied four iron oxide nanoparticles, one food pigment E172 and the ionic control FeSO4 regarding dissolution in biological media, uptake and transport, and cellular effects in vitro in human intestinal Caco-2 and HepaRG hepatocarcinoma cells. The iron oxide nanoparticles passed the gastrointestinal passage without dissolution and reached the intestine in the form of particles. Minor uptake was seen into Caco-2 cells but almost no transport to the basolateral site was detected for any of the tested particles. HepaRG cells showed higher particle uptake. Caco-2 cells showed no alterations in reactive oxygen species production, apoptosis, or mitochondrial membrane potential, whereas two particles induced apoptosis in HepaRG cells, and one altered mitochondrial membrane potential at non-cytotoxic concentrations. No correlation between physicochemical particle characteristics and cellular effects was observed, thus emphasizing the need for case-by-case assessment of iron oxide nanoparticles. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02960-7.

The structural layers around oocytes make it difficult to deliver drugs aimed at treating infertility. In this study, we sought to identify nanoparticles (NPs) that could easily pass through zona pellucida (ZP), a special layer around oocytes, for use as a drug delivery carrier. Three types of NPs were tested: quantum dot NPs, PE-polyethylene glycol (PEG)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (PEG/PL), and tetramethylrhodamine-loaded PLGA NPs (TRNPs). When mouse oocytes were treated with NPs, only TRNPs could fully pass through the ZP and cell membrane. To assess the effects of TRNPs on fertility and potential nanotoxicity, we performed mRNA sequencing analysis to confirm their genetic safety. We established a system to successfully internalize TRNPs into oocytes. The genetic stability and normal development of TRNP-treated oocytes and embryos were confirmed. These results imply that TRNPs can be used as a drug delivery carrier applicable to germ cells.

The emergence of nanotechnology as a key enabling technology over the past years has opened avenues for new and innovative applications in nanomedicine. From the business aspect, the nanomedicine market was estimated to worth USD 293.1 billion by 2022 with a perception of market growth to USD 350.8 billion in 2025. Despite these opportunities, the underlying challenges for the future of engineered nanomaterials (ENMs) in nanomedicine research became a significant obstacle in bringing ENMs into clinical stages. These challenges include the capability to design bias-free methods in evaluating ENMs’ toxicity due to the lack of suitable detection and inconsistent characterization techniques. Therefore, in this literature review, the state-of-the-art of engineered nanomaterials in nanomedicine, their toxicology issues, the working framework in developing a toxicology benchmark and technical characterization techniques in determining the toxicity of ENMs from the reported literature are explored.

Particle morphology can affect the performance of an electrostatic precipitator air–liquid interface (ESP-ALI) cell exposure system and the resulting cell toxicity. In this study, three types of monodisperse aerosols – spherical sucrose particles, nonspherical align soot aggregates, and nanosilver aggregates/agglomerates – were selected to evaluate the collection efficiency at flow rates ranging from 0.3 to 1.5 lpm. To quantify the particle morphology, the fractal dimensions (Df) of the tested aerosols were characterized. The penetration of fine particles (dp = 100–250 nm) under different operating conditions was correlated with a characteristic exponential curve using the dimensionless drift velocity (Vc/Vavg,r) as the scaling parameter. For nanoparticles (NPs, dp nm) with different particle morphologies, the particle penetrations in the ESP-ALI were similar, but their diffusion losses were not negligible. In contrast, for fine particles, the collection efficiency of soot nanoaggregates (Df = 2.29) was higher than that of spherical sucrose particles. This difference might be due to the simultaneous influences of the electric field-induced and flow field-induced alignment. Furthermore, based on Zhibin and Guoquan’s Deutsch model, a quadratic equation was applied to fit the experimental data and to predict the performance of the ESP-ALI.

Advances in cutting-edge technologies such as nano- and biotechnology have created an opportunity for re-engineering existing materials and generating new nano-scale products that can function beyond the limits of conventional ones. While the step change in the properties and functionalities of these new materials opens up new possibilities for a broad range of applications, it also calls for structural modifications to existing safety assessment processes that are primarily focused on bulk material properties. Decades after the need to modify existing risk management practices to include nano-specific behaviors and exposure pathways was recognized, relevant policies for evaluating, and controlling health risks of nano-enabled materials is still lacking. This review provides an overview of current progress in the field of nanobiotechnology rather than intentions and aspirations, summarizes long-recognized but still unresolved issues surrounding materials safety at the nanoscale, and discusses key barriers preventing generation and integration of reliable data in bio/nano-safety domain. Particular attention is given to nanostructured materials that are commonly used in biomedical applications.

Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer's disease, Parkinson's disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.

The current study aims to check various behavioural, developmental, cytotoxic, and genotoxic effects of Fe3O4-GG nanocomposite (GGNCs) on Drosophila melanogaster. Fe3O4 nanoparticles were prepared by the chemical co-precipitation method and cross-linked with guargum nanoparticles to prepare the nanocomposites. The nanocomposites were characterized by using transmission electron microscopy (TEM), X-ray diffraction (XRD), and FTIR techniques. To investigate the biomolecular interaction, GGNCs was further tagged with Fluorescein isothiocyanate. Various concentrations of nanocomposites were mixed with the food and flies were allowed to complete the life cycle. The life cycle of the flies was studied as a function of various concentrations of GGNCs. The 1st instar larvae after hatching from the egg start eating the food mixed with GGNCs. The 3rd instar larvae were investigated for various behavioural and morphological abnormalities within the gut. The 3rd instar larva has defective crawling speed, crawling path, and more number of micronuclei within the gut. Similarly, in adult flies thermal sensitivity, climbing behaviour was found to be altered. In adult flies, a significant reduction in body weight was found which is further correlated with variation of protein, carbohydrate, triglyceride, and antioxidant enzymes. Altogether, the current study suggests GGNCs as a non-genotoxic nanoparticle for various biological applications.

The unique properties of magnetic iron oxide nanoparticles determined their widespread use in medical applications, the food industry, textile industry, which in turn led to environmental pollution. These factors determine the long-term nature of the effect of iron oxide nanoparticles on the body. However, studies in the field of chronic nanotoxicology of magnetic iron particles are insufficient and scattered. Studies show that toxicity may be increased depending on oral and inhalation routes of administration rather than injection. The sensory nerve pathway can produce a number of specific effects not seen with other routes of administration. Organ systems showing potential toxic effects when injected with iron oxide nanoparticles include the nervous system, heart and lungs, the thyroid gland, and organs of the mononuclear phagocytic system (MPS). A special place is occupied by the reproductive system and the effect of nanoparticles on the health of the first and second generations of individuals exposed to the toxic effects of iron oxide nanoparticles. This knowledge should be taken into account for subsequent studies of the toxicity of iron oxide nanoparticles. Particular attention should be paid to tests conducted on animals with pathologies representing human chronic socially significant diseases. This part of preclinical studies is almost in its infancy but of great importance for further medical translation on nanomaterials to practice.

With the increasing production and application of engineered amorphous silica nanoparticles (aSiNPs), people have more opportunities to be exposed to aSiNPs. However, the knowledge of its adverse health effects and related mechanisms is still limited, compared with the well-studied crystalline micron-sized silica. Since small differences in the physical-chemical properties of nanoparticles could cause significant differences in the toxic effect, it is important to distinguish how these variations influence the outcoming toxicity. Notably, particle size, as one of the essential characterizations of aSiNPs, is relevant to its biological activities. Thus, the aim of this systematic review was to summarize the relationship between the particle size of aSiNPs and its adverse biological effects. In order to avoid the influence of complicated in vivo experimental conditions on the toxic outcome, only in vitro toxicity studies which reported on the cytotoxic effect of different sizes aSiNPs were included. After the systematic literature retrieval, selection, and quality assessment process, 76 eligible scientific papers were finally included in this review. There were 76% of the studies that concluded a size-dependent cytotoxicity of aSiNPs, in which smaller-sized aSiNPs possessed greater toxicity. However, this trend could be modified by certain influence factors, such as the synthetic method of aSiNPs, particle aggregation state in cell culture medium, toxicity endpoint detection method, and some other experimental conditions. The effects of these influence factors on the size-dependent cytotoxicity of aSiNPs were also discussed in detail in the present review.

Background The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated. Methods Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy. Results Within 30 min, both SiNPs (10-8-10-6 g/mL) did not affect the resting potential and IK1 channels. SiNP-100 increased the action potential amplitude (APA) and the INa current density, but SiNP-20 decreased APA and INa density. SiNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SiNPs (10-6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4-10 mg/kg) and SiNP-20 (4-30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice. Conclusion SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the INa and Ito channels and Ca2+ homeostasis but not IK1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.

Background Metallic nanoparticles (NPs) are highly exploited in manufacturing and medical processes in a broad spectrum of industrial applications and in the academic sectors. Several studies have suggested that many metallic nanomaterials including those derived by silver (Ag) are entering the ecosystem to cause significant toxic consequences in cell culture and animal models. However, ecotoxicity studies are still receiving limited attention when designing functionalized and non.-functionalized AgNPs. Objective This study aimed to investigate different ecotoxicological profiles of AgNPs, which were analyzed in two different states: in pristine form uncoated AgNPs and coated AgNPs with the antimicrobial peptide indolicidin. These two types of AgNPs are exploited for a set of different tests using Daphnia magna and Raphidocelis subcapitata, which are representatives of two different levels of the aquatic trophic chain, and seeds of Lepidium sativum, Cucumis sativus and Lactuca sativa. Results Ecotoxicological studies showed that the most sensitive organism to AgNPs was crustacean D. magna, followed by R. subcapitata and plant seeds, while AgNPs coated with indolicidin (IndAgNPs) showed a dose-dependent decreased toxicity for all three. Conclusion The obtained results demonstrate that high ecotoxicity induced by AgNPs is strongly dependent on the surface chemistry, thus the presence of the antimicrobial peptide. This finding opens new avenues to design and fabricate the next generation of metallic nanoparticles to ensure the biosafety and risk of using engineered nanoparticles in consumer products.

Bystander effects in biological systems are the responses shown by nontargeted neighboring cells, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of nanomaterial-induced bystander effects remain largely unknown. A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS2 nanosheets (representative transition-metal dichalcogenide nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS2 nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS2 nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-β1 played an important mediator in the bystander effects. Importantly, WS2 nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to endotoxin. This study improves the current understanding of bio-nano interactions and highlights the importance of neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.

We report on the evaluation of iron content and biodistribution in zebrafish larvae (Danio rerio) exposed to dextran-coated superparamagnetic iron oxide nanoparticles (SPION-DX) using the micro-PIXE technique. We compare results of elemental 2D maps and Fe quantification obtained from two different sample preparation procedures: one using sagittal slices prepared by cryo-sectioning and another using entire dehydrated larvae. Independently of the preparation method used, the Fe content in the tissues of exposed animals is significantly higher than in the controls, but the increase is not proportional to the exposure level. In addition, 2D elemental maps show a somewhat homogeneous Fe distribution in the larvae, with some samples showing a slight enhancement in Fe content near the gut. From the PIXE data a curve correlating the exposure (nanoparticle concentration in the fish water) to the iron content in the body was obtained, which shows a saturation trend towards high exposure doses.

Quantum Dots (QDs) like Cadmium Sulphide have exciting applications, consequent to their size-dependent optical properties. This compound is used as a pigment in papers, paint, and it can also be found in solar cells. Due to the high use of nanoparticles in society, there is a significant concern in the scientific community about the potential toxicity of these nanomaterials in aquatic environments. According to this main problem, we have a theoretical assumption that Cadmium Sulphide (CdS) particles at nanoscale are more toxic than those in macroscale (bulk), and a higher concentration means higher toxicity. To verify its toxicity in the aquatic environment, first, we need to make sure the nanoparticles are soluble in water. Based in the mentioned before, the objectives of this research were: (i) synthesize Cadmium Sulphide QDs in aqueous phase in presence of biocompatible molecules like L-Glutathione and N-Acetyl-L-cysteine, (ii) characterize the quantum dots optically, structurally and morphologically and; (iii) evaluate the toxicity of Cadmium Sulphide in biological systems. CdS, L-Glutathione-covered CdS and N-Acetyl-L-Cysteine-covered CdS evidenced shoulder peaks at 473 nm (2.40 eV), 450 nm (2.62 eV) and, 381 (3.03 eV) nm, respectively. A broad and high emission peak centered at 545 nm was observed for CdS Nps covered with N-acetyl-L cysteine; whereas as QDs without cover and those covered with L-glutathione showed weak peaks in the visible range (470 nm-650 nm). The presence of L-Glutathione or N-Acetyl-L-cysteine on the quantum dots surface was verified by Infrared Spectroscopy. Energy Dispersive X-Ray Spectroscopy (EDX) assays evidenced the chemical composition of produced nanostructures having 57.91% of S and 42.09% of Cd. The morphology and the size were carried out by High-Resolution Transmission Electron Microscopy (HR-TEM). In this way, nanoparticles were spherical and with a size of ~3 nm. Toxicity results evidence that nanoparticles covered with N-Acetyl-L-Cysteine had a negative interaction in marine organisms at concentrations higher than 700 ppm, after 24 or 48 hours of contact. Also, CdS bulk showed absence of toxicity to marine crustaceans.

Silver nanoparticles (Ag NPs) are widely used in nanomedicine, pharmaceutical products, industry and other consumer products owing to their unique physiochemical properties with probable potential risk to human health and the ecosystems. The aim of this work was to investigate the in-life morphological effects, biochemical, histological and histochemical alterations that might be induced by variable sizes of Ag NPs in hepatic, renal and testicular tissues with the hypothesis that variable sizes of nano-Ag could induce variable effects in the vital organs. Five groups of adult healthy male mice (BALB/C) were exposed to 35 intraperitoneal injections of Ag NPs (1 mg/kg bw) using five different particle sizes (10, 20, 40, 60 and 100 nm). All mice were subjected to in-life morphometric, biochemical, histological and histochemical analysis. The findings demonstrated that Ag NPs could induce alterations in the average body weight gain, food consumption, water intake and organ indices. In addition, these NPs significantly altered hepatic and renal biomarkers. Moreover, Ag NPs produced ground glass hepatocyte cytoplasm, with mitotic activity, nuclear alterations, degeneration, glycogen depletion and inflammatory cells infiltration in the liver. The kidneys of treated mice exhibited proximal renal tubules degeneration, distal renal tubules regeneration, glomerular shrinkage, Bowman’s capsule thickening and interstitial inflammation. The testicular tissues demonstrated spermatocyte sloughing and spermatid giant cell formation. The findings together indicated that Ag NPs could interact with the anatomical structures of the liver, kidney and testis in ways that could induce injury. In addition, the results indicated that smaller Ag NPs posed a greater potential risk than the larger ones, which might be associated with their behaviour, dissolution rate, bioavailability and their probable variable toxicokinetics.

Recent technological advances have introduced diverse engineered nanoparticles (ENPs) into our air, water, medicine, cosmetics, clothing, and food. However, the health and environmental effects of these increasingly common ENPs are still not well understood. In particular, potential neurological effects are one of the most poorly understood areas of nanoparticle toxicology (nanotoxicology), in that low-to-moderate neurotoxicity can be subtle and difficult to measure. Culturing primary neuron explants on planar microelectrode arrays (MEAs) has emerged as one of the most promising in vitro techniques with which to study neuro-nanotoxicology, as MEAs enable the fluorescent tracking of nanoparticles together with neuronal electrical activity recording at the submillisecond time scale, enabling the resolution of individual action potentials. Here we examine the dose-dependent neurotoxicity of dextran-coated iron oxide nanoparticles (dIONPs), a common type of functionalized ENP used in biomedical applications, on cultured primary neurons harvested from postnatal day 0–1 mouse brains. A range of dIONP concentrations (5–40 µg/ml) were added to neuron cultures, and cells were plated either onto well plates for live cell, fluorescent reactive oxidative species (ROS) and viability observations, or onto planar microelectrode arrays (MEAs) for electrophysiological measurements. Below 10 µg/ml, there were no dose-dependent cellular ROS increases or effects in MEA bursting behavior at sub-lethal dosages. However, above 20 µg/ml, cell death was obvious and widespread. Our findings demonstrate a significant dIONP toxicity in cultured neurons at concentrations previously reported to be safe for stem cells and other non-neuronal cell types.

Multi-walled carbon nanotubes (MWCNTs) are known to induce pulmonary inflammatory effects through stimulating pro-inflammatory cytokine secretion from alveolar macrophages. Despite extensive studies on MWCNTs’ pro-inflammatory reactivity, the understanding of molecular mechanisms involved is still incomplete. In this study, we investigated hemichannel’s involvement in MWCNTs-induced macrophage IL-1β release. Our results showed that the unmodified and COOH MWCNTs could induce ATP release and ATP-P2X7R axis-dependent IL-1β secretion from THP-1 macrophages. By using various inhibitors, we confirmed that the MWCNTs-induced ATP release was primarily through hemichannels. EtBr dye uptake assay detected significant hemichannels opening in MWCNTs exposed THP-1 macrophages. Inhibition of hemichannels by CBX, 43Gap27, or 10Panx1 pretreatment results in decreased ATP and IL-1β release. The addition of ATP restored the reduced IL-1β secretion level from hemichannel inhibition. We also confirmed with five other types of MWCNTs that the induction of hemichannels by MWCNTs strongly correlates with their capacity to induce IL-1β secretion. Taken together, we conclude that hemichannels-mediated ATP release and subsequent NLRP3 inflammasome activation through P2X7R may be one mechanism by which MWCNTs induce macrophage IL-1β secretion. Our findings may provide a novel molecular mechanism for MWCNTs induced IL-1β secretion.

Titanium dioxide (TiO2) nanostructures are one of the most plentiful compounds that have emerged in various fields of technology such as medicine, energy and biosensing. Various TiO2 nanostructures (nanotubes [NTs] and nanowires) have been employed in photoelectrochemical (PEC) biosensing applications, greatly enhancing the detection of targets. TiO2 nanostructures, used as reinforced material or coatings for the bare surface of titanium implants, are excellent additive materials to compensate titanium implants deficiencies-like poor surface interaction with surrounding tissues-by providing nanoporous surfaces and hierarchical structures. These nanostructures can also be loaded by diversified drugs-like osteoporosis drugs, anticancer and antibiotics-and used as local drug delivery systems. Furthermore, TiO2 nanostructures and their derivatives are new emerging antimicrobial agents to overcome human pathogenic microorganisms. However, like all other nanomaterials, toxicity and biocompatibility of TiO2 nanostructures must be considered. This review highlights recent advances, along with the properties and numerous applications of TiO2-based nanostructure compounds in nano biosensing, medical implants, drug delivery and antibacterial fields. Moreover, in the present study, some recent advances accomplished on the pharmaceutical applications of TiO2 nanostructures, as well as its toxicity and biocompatibility, are presented.

Introduction Nanoparticles are at the forefront of rapidly developing nanotechnology and have gained much attention for their application as an effective drug delivery system and as a mediated therapeutic agent for cancer. However, the cytotoxicity of nanoparticles is still relatively unknown and, therefore, additional study is required in order to elucidate the potential toxicity of these nanoparticles on cells. Materials and methods Thus, the following work aimed to investigate the capability of Beta vulgaris (beetroot) water extract (BWE; 200 mg/kg) to protect hepatic tissue following silver nanoparticles (AgNPs; 80 mg/kg; >100 nm) intoxication in male rats. Results AgNPs-intoxication elevated the liver function markers - including serum transaminases and alkaline phosphatase activities - and decreased serum levels of albumin and total proteins, in addition to disturbing the oxidation homeostasis. This is evidenced by the increased lipid peroxidation, the depleted glutathione, and the suppressed activity of superoxide dismutase and catalase. In addition, an apoptotic reaction was observed following AgNPs treatment, as indicated by the up-regulation of p53 and down-regulating Bcl-2 expressions, examined by the immunohistochemistry method. Furthermore, AgNPs exhibited a marked elevation in liver DNA damage that was indicated by an increase in tail length, tail DNA% and tail movement. However, BWE eliminated the biochemical and histological alterations, reflecting its hepatoprotection effect in response to AgNPs. Discussion Collectively, the present data suggest that BWE could be used following AgNPs as a potential therapeutic intervention to minimize AgNPs-induced liver toxicity.

Breast cancer remains as a concerning global health issue, being the second leading cause of cancer deaths among women in the United States (US) in 2019. Therefore, there is an urgent and substantial need to explore novel strategies to combat breast cancer. A potential solution may come from the use of cancer nanotechnology, an innovative field of study which investigates the potential of nanomaterials for cancer diagnosis, therapy, and theranostic applications. Consequently, the theranostic functionality of cancer nanotechnology has been gaining much attention between scientists during the past few years and is growing exponentially. The use of biosynthesized gold nanoparticles (AuNPs) has been explored as an efficient mechanism for the treatment of breast cancer. The present study supposed a global systematic review to evaluate the effectiveness of biogenic AuNPs for the treatment of breast cancer and their anticancer molecular mechanisms through in vitro studies. Online electronic databases, including Cochrane, PubMed, Scopus, Web of Science, Science Direct, ProQuest, and Embase, were searched for the articles published up to July 16, 2019. Our findings revealed that plant-mediated synthesis was the most common approach for the generation of AuNPs. Most of the studies reported spherical or nearly spherical -shaped AuNPs with a mean diameter less than 100 nm in size. A significantly larger cytotoxicity was observed when the biogenic AuNPs were tested towards breast cancer cells compared to healthy cells. Moreover, biogenic AuNPs demonstrated significant synergistic activity in combination with other anticancer drugs through in vitro studies. Although we provided strong and comprehensive preliminary in vitro data, further in vivo investigations are required to show the reliability and efficacy of these NPs in animal models.

Actually, many discussions on the potential risks of silver nanoparticles (AgNPs) have been reported; however, unfortunately, very few considered the great differences between the nature of silver and sources of their syntheses. All data suggested that the effects on toxicity of AgNPs are related to the combination of the specific properties of AgNPs. In this context, this review presents and discusses the recent progress in the nanotoxicity of AgNPs, obtained by different biogenic synthetic protocols, in comparison with chemical synthetic methods, driving to the formation of nanoparticles with diverse structures, and size distributions. Biogenic syntheses of AgNPs using several biological sources and other chemical agents are presented and discussed. Toxicity in different animals is also presented and discussed. By considering the actual state of the art, it can be assumed that oral, intravenous and inhalation doses of AgNPs from 0.1 to 2 mg/Kg in mice and rats are considered a safe administration. In terms of ecotoxicity, it is more concerning since many of the in vivo assays showed a very low lethal dose, i.e., 50% (LD50). Therefore, we have to be very careful with the AgNPs residues in the environment.

As a result of their biodegradability and biocompatibility, various nanoparticles using poly(lactic-co-glycolic acid) (PLGA) as a copolymer have shown promising results in biomedical engineering fields, including molecular imaging and drug delivery. However, the potential nanotoxicity of PLGA-based nanoparticles in the environment was poorly understood. Measurement of bacterial nitrification activities and changes in the soil microbial community are both critical parameters that should be used to evaluate potential distrurbances in the functioning of the environmental ecosystem. This study aimed to investigate the impact of PLGA nanoparticles with different zeta-potentials on nitrifying bacterial communities in the soil environment. In pure culture studies, the ammonia oxidation was inhibited by higher than 50% when PLGA cocentration is more than 0.05 mg/L or more regardless of zeta potential and exposure time, but the negligible effects were observed on the nitrite oxidation by most conditions. In the soil microcosm experiment, at the 0.05 concentration of the oparticles, the ammonia and nitrite oxidation were inhibited by more than 50% on the first day regardless of the nanoparticle composition, but all the activity was recovered after 14 days. These results provide a fundamental information on the toxcity of PLGA nanparticles on ecologcial function.

Introduction Indium phosphide (InP) quantum dots (QDs) have shown a broad application prospect in the fields of biophotonics and nanomedicine. However, the potential toxicity of InP QDs has not been systematically evaluated. In particular, the effects of different surface modifications on the biodistribution and toxicity of InP QDs are still unknown, which hinders their further developments. The present study aims to investigate the biodistribution and in vivo toxicity of InP/ZnS QDs. Methods Three kinds of InP/ZnS QDs with different surface modifications, hQDs (QDs-OH), aQDs (QDs-NH2), and cQDs (QDs-COOH) were intravenously injected into BALB/c mice at the dosage of 2.5 mg/kg BW or 25 mg/kg BW, respectively. Biodistribution of three QDs was determined through cryosection fluorescence microscopy and ICP-MS analysis. The subsequent effects of InP/ZnS QDs on histopathology, hematology and blood biochemistry were evaluated at 1, 3, 7, 14 and 28 days post-injection. Results These types of InP/ZnS QDs were rapidly distributed in the major organs of mice, mainly in the liver and spleen, and lasted for 28 days. No abnormal behavior, weight change or organ index were observed during the whole observation period, except that 2 mice died on Day 1 after 25 mg/kg BW hQDs treatment. The results of H&E staining showed that no obvious histopathological abnormalities were observed in the main organs (including heart, liver, spleen, lung, kidney, and brain) of all mice injected with different surface-functionalized QDs. Low concentration exposure of three QDs hardly caused obvious toxicity, while high concentration exposure of the three QDs could cause some changes in hematological parameters or biochemical parameters related to liver function or cardiac function. More attention needs to be paid on cQDs as high-dose exposure of cQDs induced death, acute inflammatory reaction and slight changes in liver function in mice. Conclusion The surface modification and exposure dose can influence the biological behavior and in vivo toxicity of QDs. The surface chemistry should be fully considered in the design of InP-based QDs for their biomedical applications.

Applications of nanomaterials cause a general concern on their toxicity when they intentionally (such as in medicine) or unintentionally (environment exposure) enter into the human body. As a special subpopulation, pregnant women are more susceptible to nanoparticle (NP)-induced toxicity. More importantly, prenatal exposures may affect the entire life of the fetus. Through blood circulation, NPs may cross placental barriers and enter into fetus. A cascade of events, such as damage in placental barriers, generation of oxidative stress, inflammation, and altered gene expression, may induce delayed or abnormal fetal development. The physicochemical properties of NPs, exposure time, and other factors directly affect nanotoxicity in pregnant populations. Even though results from animal studies cannot directly extrapolate to humans, compelling evidence has already shown that, for pregnant women, caution must be taken when dealing with nanomedicines or NP pollutants.

Background As one of the most widely produced engineered nanomaterials, titanium dioxide nanoparticles (nano-TiO2) are used in biomedicine and healthcare products, and as implant scaffolds; therefore, the toxic mechanism of nano-TiO2 has been extensively investigated with a view to guiding application. Three-dimensional (3D) spheroid models can simplify the complex physiological environment and mimic the in vivo architecture of tissues, which is optimal for the assessment of nano-TiO2 toxicity under ultraviolet A (UVA) irradiation. Methods and results In the present study, the toxicity of nano-TiO2 under UVA irradiation was investigated in 3D H22 spheroids cultured in fibrin gels. A significant reduction of approximately 25% in spheroid diameter was observed following treatment with 100 μg/mL nano-TiO2 under UVA irradiation after seven days of culture. Nano-TiO2 under UVA irradiation triggered the initiation of the TGF-β/Smad signaling pathway, increasing the expression levels of TGF-β1, Smad3, Cdkn1a, and Cdkn2b at both the mRNA and protein level, which resulted in cell cycle arrest in the G1 phase. In addition, nano-TiO2 under UVA irradiation also triggered the production of reactive oxygen species (ROS), which were shown to be involved in cell cycle regulation and the induction of TGF-β1 expression. Conclusion Nano-TiO2 under UVA irradiation induced cell cycle arrest in the G1 phase and the formation of smaller spheroids, which were associated with TGF-β/Smad signaling pathway activation and ROS generation. These results reveal the toxic mechanism of nano-TiO2 under UVA irradiation, providing the possibility for 3D spheroid models to be used in nanotoxicology studies.

We have designed an experimental study dedicated to silver nanotoxicity using a suspension of citrate-silver nanoparticles, obtained by photochemical reduction. Fine granularity of generally symmet...

Aim: To demonstrate that cobalt nanoparticles doses are safe for use in humans and to understand the consequences of the particulate effects, which may persist inside the cells. Materials & methods: Human adipose stem cells were used. We evaluated cell recovery by viability test, morphology and ultrastructure using electronic and optical microscopy, while gene expression was assessed utilizing real-time PCR. Results: After exposure, most stem cells recovered their normal function. Co3O4-nanoparticles remained inside the cell for the entirety of the considered time. A slight modification of gene expression was observed in the exposed cells. Conclusion: After exposure to 100 M cobalt nanoparticles, most cells returned to normal function. Nanoparticle toxicity was due to ions released by dissolution as well as from the nanoparticles themselves.

Nanocomposites as drug delivery systems (e.g., metal nanoparticles) are being exploited for several applications in the biomedical field, from therapeutics to diagnostics. Green nanocomposites stand for nanoparticles of biocompatible, biodegradable and non-toxic profiles. When using metal nanoparticles for drug delivery, the question of how hazardous these virus-sized particles can be is posed, due to their nanometer size range with enhanced reactivity compared to their respective bulk counterparts. These structures exhibit a high risk of being internalized by cells and interacting with the genetic material, with the possibility of inducing DNA damage. The Comet Assay, or Single-Cell Gel Electrophoresis (SCGE), stands out for its capacity to detect DNA strand breaks in eukaryotic cells. It has huge potential in the genotoxicity assessment of nanoparticles and respective cells interactions. In this review, the Comet assay is described, discussing several examples of its application in the genotoxicity evaluation of nanoparticles commonly administered in a set of routes (oral, skin, inhaled, ocular and parenteral administration). In the nanoparticles boom era, where guidelines for their evaluation are still very limited, it is urgent to ensure their safety, alongside their quality and efficacy. Comet assay or SCGE can be considered an essential tool and a reliable source to achieve a better nanotoxicology assessment of metal nanoparticles used in drug delivery., This work was funded by the Portuguese Science and Technology Foundation (FCT) from the Ministry of Science and Technology (MCTES), through the projects UIDB/04469/2020 (CEB strategic fund) and UIDB/04033/2020 (CITAB), co-funded by European Funds (PRODER/COMPETE) and FEDER, under the Partnership Agreement PT2020. The work was also supported by the National Science Centre within the MINIATURA 4 for single research activity (grant No: 2020/04/X/ST5/00789) and by the START 2021 Program of the Foundation for Polish Science (FNP) granted to Dr. Aleksandra Zielińska, info:eu-repo/semantics/publishedVersion

Translation of advanced cell-based assays exhibiting a higher degree of automation, miniaturization, and integration of complementary sensing functions is mainly limited by the development of industrial-relevant prototypes that can be readily produced in larger volumes. Despite the increasing number of academic publications in recent years, the manufacturability of these microfluidic cell cultures systems is largely ignored, thus severely restricting their implementation in routine toxicological applications. We have developed a dual-sensor integrated microfluidic cell analysis platform using industrial specifications, materials, and fabrication methods to conduct risk assessment studies of engineered nanoparticles to overcome this academic-industrial gap. Non-invasive and time-resolved monitoring of cellular oxygen uptake and metabolic activity (pH) in the absence and presence of nanoparticle exposure is accomplished by integrating optical sensor spots into a cyclic olefin copolymer (COC)-based microfluidic platform. Results of our nanotoxicological study, including two physiological cell barriers that are essential in the protection from exogenous factors, the intestine (Caco-2) and the vasculature (HUVECs) showed that the assessment of the cells' total energy metabolism is ideally suited to rapidly detect cytotoxicities. Additional viability assay verification using state-of-the-art dye exclusion assays for nanotoxicology demonstrated the similarity and comparability of our results, thus highlighting the benefits of employing a compact and cost-efficient microfluidic dual-sensor platform as a pre-screening tool in nanomaterial risk assessment and as a rapid quality control measure in medium to high-throughput settings.

Understanding the uptake of nanoparticles (NPs) by different types of cellular membranes plays a pivotal role in the design of NPs for medical applications and in avoiding adverse effects that result in nanotoxicity. Yet, the role of key design parameters, such as the bare NP material, NP size and surface reactivity, and the nature of NP coatings, in membrane remodelling and uptake mechanisms is still very poorly understood, particularly towards the lower range of NP dimensions that are beyond the experimental imaging resolution. The same can be said about the role of a particular membrane composition. Here, we systematically employ biased and unbiased molecular dynamics simulations to calculate the binding energy for three bare materials (Ag/SiO2/TiO2) and three NP sizes (1/3/5 nm diameter) with a representative lung surfactant membrane, and to study their binding kinetics. The calculated binding energies show that irrespective of size, Ag nanoparticles bind very strongly to the bilayer, while the NPs made of SiO2 or TiO2 experience very low to no binding. The unbiased simulations provide insight into how the NPs and membrane affect each other in terms of the solvent-accessible surface area (SASA) of the NPs and the defect types and fluidity of the membrane. Using these systematic fine-grained results in coarsening procedures will pave the way for simulations considering NP sizes that are well beyond the membrane thickness, i.e. closer to experimental dimensions, for which different binding characteristics and more significant membrane remodelling are expected.

Assessing the risks of nanomaterials/nanoparticles (NMs/NPs) under various environmental conditions requires a more systematic approach, including the comparison of effects across many NMs with identified different but related characters/descriptors. Hence, there is an urgent need to provide coherent (eco)toxicological datasets containing comprehensive toxicity information relating to a diverse spectra of NPs characters. These datasets are test benches for developing holistic methodologies with broader applicability. In the present study we assessed the effects of a custom design Fe-doped TiO2 NPs library, using the soil invertebrate Enchytraeus crypticus (Oligochaeta), via a 5-day pulse via aqueous exposure followed by a 21-days recovery period in soil (survival, reproduction assessment). Obviously, when testing TiO2, realistic conditions should include UV exposure. The 11 Fe-TiO2 library contains NPs of size range between 5-27 nm with varying %Fe (enabling the photoactivation of TiO2 at energy wavelengths in the visible-light range). The NPs were each described by 122 descriptors, being a mixture of measured and atomistic model descriptors. The data were explored using single and univariate statistical methods, combined with machine learning and multiscale modelling techniques. An iterative pruning process was adopted for identifying automatically the most significant descriptors. TiO2 NPs toxicity decreased when combined with UV. Notably, the short-term water exposure induced lasting biological responses even after longer-term recovery in clean exposure. The correspondence with Fe-content correlated with the band-gap hence the reduction of UV oxidative stress. The inclusion of both measured and modelled materials data benefitted the explanation of the results, when combined with machine learning. This journal is

Metal nanoparticles have been extensively investigated for different types of pharmaceutical applications. However, their use has raised some concerns about their toxicity involving the increase of reactive oxygen species causing cellular apoptosis. Therefore, in this review we summarize the most relevant toxicity mechanisms of gold, silver, copper and copper oxide nanoparticles as well as production methods of metal nanoparticles. Parameters involved in their toxicity such as size, surface charge and concentration are also highlighted. Moreover, a critical revision of the literature about the strategies used to reduce the toxicity of this type of nanoparticles is carried out throughout the review. Additionally, surface modifications using different coating strategies, nanoparticles targeting and morphology modifications are deeply explained., This work was funded by the Portuguese Science and Technology Foundation (FCT) from the Ministry of Science and Technology (MCTES), European Social Fund (FSE) of EU, through the project UIDB/04469/2020 (CEB strategic fund), co-funded by European Funds (PRODER/COMPETE) and FEDER, under the Partnership Agreement PT2020., info:eu-repo/semantics/publishedVersion

Exposure to nanoparticles by various routes results in size-dependent translocation of nanoparticles to the systemic circulation and subsequent accumulation in the liver. The purpose of this study was to determine possible adverse effects in the liver of long-lasting nanoparticle presence in the organ. Mice exposed to a single dose (162 µg/animal equivalent to 9 mg/kg body weight) of TiO2, CeO2 or carbon black nanoparticles by intratracheal instillation or intravenous injection, resulting in relatively low or high liver burdens, were followed for 1, 28 or 180 days. Clinical appearance, feed intake, body and liver weights, hematological indices, and transaminases and alkaline phosphatase activities were unaffected by exposure. Exposure-related foreign material persisted in the liver up to 180 days after intratracheal and intravenous exposure, mainly in sinusoids, near Kupffer cells, or around blood vessels. Increased incidences of histological findings after intratracheal or intravenous exposure included: initially, prominent nuclei of Kupffer cells, the apparent increase in binucleate hepatocytes (TiO2 and carbon black) and inflammatory infiltrations (CeO2), later, cytoplasmic vacuolation, pyknosis and necrosis, especially for CeO2. Thus, neither low nor high nanoparticle burden in the liver affected enzymatic markers of liver injury, but indications of exposure-related necrotic changes, particularly for CeO2 nanoparticles, were noted.

It is acknowledged that the physicochemical properties of nanomaterials (NMs) have an impact on their toxicity and, eventually, their pathogenicity. These properties may include the NMs’ surface chemical composition, size, shape, surface charge, surface area, and surface coating with ligands (which can carry different functional groups as well as proteins). Nanotopography, defined as the specific surface features at the nanoscopic scale, is not widely acknowledged as an important physicochemical property. It is known that the size and shape of NMs determine their nanotopography which, in turn, determines their surface area and their active sites. Nanotopography may also influence the extent of dissolution of NMs and their ability to adsorb atoms and molecules such as proteins. Consequently, the surface atoms (due to their nanotopography) can influence the orientation of proteins as well as their denaturation. However, although it is of great importance, the role of surface topography (nanotopography) in nanotoxicity is not much considered. Many of the issues that relate to nanotopography have much in common with the fundamental principles underlying classic catalysis. Although these were developed over many decades, there have been recent important and remarkable improvements in the development and study of catalysts. These have been brought about by new techniques that have allowed for study at the nanoscopic scale. Furthermore, the issue of quantum confinement by nanosized particles is now seen as an important issue in studying nanoparticles (NPs). In catalysis, the manipulation of a surface to create active surface sites that enhance interactions with external molecules and atoms has much in common with the interaction of NP surfaces with proteins, viruses, and bacteria with the same active surface sites of NMs. By reviewing the role that surface nanotopography plays in defining many of the NMs’ surface properties, it reveals the need for its consideration as an important physicochemical property in descriptive and predictive toxicology. Through the manipulation of surface topography, and by using principles developed in catalysis, it may also be possible to make safe-by-design NMs with a reduction of the surface properties which contribute to their toxicity.

Once metal-based engineered nanoparticles (NPs) are released into the aquatic environment, they are expected to interact with other existing co-contaminants. A knowledge gap exists as to how the interaction of NPs with other co-contaminants occurs. Here we selected ZnO NPs among various NPs, with Ag ion existing as a contaminant in the aquatic environment by Ag NPs widely used. A novel modeling strategy was demonstrated enabling quantitative and predictive evaluation of the aqueous mixture nanotoxicity. Individual and binary mixture toxicity tests of ZnO NPs and silver (as AgNO3) on Daphnia magna were conducted and compared to determine whether the presence of Ag ions affects the toxicity of ZnO NPs. Binary mixture toxicity was evaluated based on the concentration addition (CA) and independent action models. The CA dose-ratio dependent model was found to be the model of best fit for describing the pattern of mixture toxicity. The MIX I and MIX III suspensions (higher ratios of ZnO NPs to AgNO3) showed a synergism, whereas the MIX II suspension (lower ratio of ZnO NPs to AgNO3) showed an antagonism. The synergistic mixture toxicity at higher ratios of ZnO NPs to AgNO3 was caused by either the physiological or metabolic disturbance induced by the excessive ionic Zn or increased transport and accumulation in D. magna via the formation of complex of ionic Ag with ZnO NPs. Therefore, the toxicity level contributed via their aggregation and physicochemical properties and the dissolved ions played a crucial role in the mixture toxicities of the NPs., GRAPHICAL ABSTRACT

Emerging applications in the field of nanotechnology are able to solve a gamut of problems surrounding the applications of agroecosystems and food technology. Nano Engineered Material (NEM) based nanosensors are important tools for monitoring plant signaling pathways and metabolism that are nondestructive, minimally invasive, and can provide real-time analysis of biotic and abiotic threats for better plant health. These sensors can measure chemical flux even at the singlemolecule level. Therefore, plant health could be monitored through nutrient management, disease assessment, plant hormones level, environmental pollution, etc. This review provides a comprehensive account of the current trends and practices for the proposed NEM related research and its (i) structural aspect, (ii) experimental design and performance as well as (iii) mechanisms of field application in agriculture and food system. This review also discusses the possibility of integration of data from NEM based nanosensors in current and emerging trends of precision agriculture, urban farming, and plant nanobionics to adopt a sustainable approach in agriculture.

The clinical utility of Rapamycin (Rapa) is limited by solubility, bioavailability, and side effects. To overcome this, our team recently reported an elastin-like polypeptide (ELP) nanoparticle with high-affinity, non-covalent drug-binding as well as integrin-mediated cellular uptake. Given the scarcity of pharmacology/toxicology studies of ELP-based drug carriers, this manuscript explores safety and efficacy of ELP-Rapa. ELP-Rapa nanoparticles tested negative for hemolysis, did not interfere in plasma coagulation nor platelet function, and did not activate the complement. Upon incubation with HepG2 cells, ELP-Rapa revealed significant cellular uptake and trafficking to acidic organelles, consistent with lysosomes. Internalized ELP-Rapa nanoparticles increased oxidative stress 4-fold compared to free drug or free ELP controls. However, mice bearing orthotopic hormone receptor positive BT-474 breast tumors, given a high dose (~10-fold above therapeutic dose) one-month administration of ELP-Rapa did not induce hepatotoxicity. On the other hand, tumor growth and mTOR-signaling was suppressed without affecting body weight. Nanoparticles assembled using ELP technology appear to be a safe and efficient strategy for delivering Rapa.

Single-walled carbon nanotubes (SWCNTs) are a group of widely used carbon-based nanomaterials (CNMs) with various applications, which have caused increasing public concerns associated with their potential toxicological effects on and risks to humans and ecosystems. In this report, we comprehensively evaluated the nanotoxicity of SWCNTs and its relationship to varying lengths, functional groups and electronic structures, by employing both a newly established quantitative toxicogenomics test and conventional phenotypic bioassays. The objective is to reveal the potential cellular toxicity and mechanisms of SWCNTs at the molecular level, and to probe their potential relationships with the SWCNTs' morphological, surface, and electronic properties. The results indicated that DNA damage and oxidative stress were the dominant mechanisms of action for all the SWCNTs, and the toxicity level and characteristics varied with length, surface functionalization and electronic structure. Distinguishable molecular toxicity fingerprints were revealed for the two SWCNTs with varying length, with the short SWCNT exhibiting a higher toxicity level than the long one. In terms of surface properties, SWCNT functionalization, namely carboxylation and hydroxylation, led to elevated overall toxicity, especially genotoxicity, as compared to the unmodified SWCNT. The carboxylated SWCNT induced a greater toxicity than the hydroxylated SWCNT. The nucleus is likely the primary target site for long, short, and carboxylated SWCNTs and mechanical perturbation is likely responsible for the DNA damage, specifically related to degradation of the DNA double helix structure. Finally, a dramatically different electronic structure-dependent toxicity was observed with the metallic SWCNT exerting a much higher toxicity than the semiconducting one which exhibited minimal toxicity among all the SWCNTs.

With the rapid development of nanotechnology, inorganic nanomaterials (NMs) have been widely applied in modern society. As human exposure to inorganic NMs is inevitable, comprehensive assessment of the safety of inorganic NMs is required. It is well known that autophagy plays dual roles in cell survival and cell death. Moreover, inorganic NMs have been proven to induce autophagy perturbation in cells. Therefore, an in-depth understanding of inorganic NMs-modulated autophagy is required for the safety assessment of inorganic NMs. This review presents an overview of a set of inorganic NMs, consisting of iron oxide NMs, silver NMs, gold NMs, carbon-based NMs, silica NMs, quantum dots, rare earth oxide NMs, zinc oxide NMs, alumina NMs, and titanium dioxide NMs, as well as how each modulates autophagy. This review emphasizes the potential mechanisms underlying NMs-induced autophagy perturbation, as well as the role of autophagy perturbation in cell fate determination. Furthermore, we also briefly review the potential roles of inorganic NMs-modulated autophagy in diagnosis and treatment of disease.

Mucosal tissues constitute the largest interface between the body and the surrounding environment and they regulate the access of molecules, supramolecular structures, particulate matter, and pathogens into it. All mucosae are characterized by an outer mucus layer that protects the underlying cells from physicochemical, biological and mechanical insults, a mono-layered or stratified epithelium that forms tight junctions and controls the selective transport of solutes across it and associated lymphoid tissues that play a sentinel role. Mucus is a gel-like material comprised mainly of the glycoprotein mucin and water and it displays both hydrophilic and hydrophobic domains, a net negative charge, and high porosity and pore interconnectivity, providing an efficient barrier for the absorption of therapeutic agents. To prolong the residence time, absorption and bioavailability of a broad spectrum of active compounds upon mucosal administration, mucus-penetrating and mucoadhesive particles have been designed by tuning the chemical composition, the size, the density, and the surface properties. The benefits of utilizing nanomaterials that interact intimately with mucosae by different mechanisms in the nanomedicine field have been extensively reported. To ensure the safety of these nanosystems, their compatibility is evaluated in vitro and in vivo in preclinical and clinical trials. Conversely, there is a growing concern about the toxicity of nanomaterials dispersed in air and water effluents that unintentionally come into contact with the airways and the gastrointestinal tract. Thus, deep understanding of the key nanomaterial properties that govern the interplay with mucus and tissues is crucial for the rational design of more efficient drug delivery nanosystems (nanomedicine) and to anticipate the fate and side-effects of nanoparticulate matter upon acute or chronic exposure (nanotoxicology). This review initially overviews the complex structural features of mucosal tissues, including the structure of mucus, the epithelial barrier, the mucosal-associated lymphatic tissues and microbiota. Then, the most relevant investigations attempting to identify and validate the key particle features that govern nanomaterial-mucosa interactions and that are relevant in both nanomedicine and nanotoxicology are discussed in a holistic manner. Finally, the most popular experimental techniques and the incipient use of mathematical and computational models to characterize these interactions are described.

Engineered nanomaterials (ENMs) have become common in the food industry, which motivates the need to evaluate ENM effects on human health. Gastrointestinal (GI) in vitro models (e.g. Caco-2, Caco-2/HT29-MTX) have been used in nanotoxicology research. However, the human gut environment is composed of both human cells and the gut microbiota. The goal of this study is to increase the complexity of the Caco-2/HT29-MTX in vitro model by co-culturing human cells with the Gram-positive, commensal Lactobacillus rhamnosus or the Gram-negative, opportunistic Escherichia coli; with the hypothesis that the presence of bacteria would ameliorate the effects of exposure to metal oxide nanoparticles (NPs) such as iron oxide (Fe(2)O(3)), silicone dioxide (SiO(2)), titanium dioxide (TiO(2)), or zinc oxide (ZnO). To understand this relationship, Caco-2/HT29-MTX cell barriers were acutely co-exposed (4 hours) to bacteria and/or NPs (pristine or in vitro digested). The activity of the brush border membrane (BBM) enzymes intestinal alkaline phosphatase (IAP), aminopeptidase-N (APN), sucrase isomaltase (SI) and the basolateral membrane enzyme (BLM) Na(+)/K(+) ATPase were assessed. Findings show that (i) the human digestion process alters the physicochemical properties of NPs, (ii) large agglomerates of NPs remain entrapped on the apical side of the intestinal barrier, which (iii) affects the activity of BBM enzymes. Interestingly, some NPs effects were attenuated in the presence of either bacterial strains. Confocal microscopy detected bacteria-NPs interactions, which may impede the NP-intestinal cell contact. These results highlight the importance of improving in vitro models to closely mimic the complexities of the human body.

The biomolecular imaging of cell-nanoparticle (NP) interactions using time-of-flight secondary ion mass spectrometry (ToF-SIMS) represents an evolving tool in nanotoxicology. In this study we present the three dimensional (3D) distribution of nanomaterials within biomolecular agglomerates using ToF-SIMS imaging. This novel approach was used to model the resistance of human alveolar A549 cells against gold (Au) ion toxicity through intra- and extracellular biomineralization. At low Au concentrations (≤1 mM HAuCl4) 3D-ToF-SIMS imaging reveals a homogenous intracellular distribution of Au-NPs in combination with polydisperse spherical NPs biomineralized in different layers on the cell surface. However, at higher precursor concentrations (≥2 mM) supplemented with biogenic spherical NPs as seeds, cells start to biosynthesize partially embedded long aspect ratio fiber-like Au nanostructures. Most interestingly, A549 cells seem to be able to sense the enhanced Au concentration. They change the chemical composition of the extracellular NP agglomerates from threonine-O-3-phosphate aureate to an arginine-Au(I)-imine. Furthermore they adopt the extracellular mineralization process from spheres to irregular structures to nanoribbons in a dose-dependent manner with increasing Au concentrations. The results achieved regarding size, shape and chemical specificity were cross checked by SEM-EDX and single particle (sp-)ICP-MS. Our findings demonstrate the potential of ToF-SIMS 3D imaging to better understand cell-NP interactions and their impact in nanotoxicology.

The study on the safety of nanomaterials in eyes is still in its early stages. In this study, we put our focus on the effect of one important nanoparticle feature - large surface area - to assess eye safety. To this end, mesoporous silica nanoparticles (MSiNPs) were for the first time employed as a model to evaluate their toxicity in eyes. The porosity of the MSiNPs endows them with a large surface area and the ability to attach to surrounding chemical or biological molecules, further enhancing their surface reactivity and toxic effects. Therefore, to better mimic MSiNP exposure in real environments, we also introduced other hazardous substances such as silver ions (Ag+) to the system and then investigated their synergistic nanotoxicity. Our results showed that the exposure to MSiNPs-Ag+ and even Ag+ at a safe dose, resulted in more significant toxicity than the MSiNPs alone, as evidenced from cell viability, apoptosis, reactive oxygen species (ROS) production, and DNA damage experiments. RNA-Sequencing analysis revealed that the mRNA surveillance signalling pathway plays a unique role in regulating MSiNPs-Ag+-induced cytotoxicity. Besides this, severe corneal damage and dry eye were observed in rat models upon exposure to MSiNPs-Ag+ compared to MSiNPs. Most importantly, we also proposed a protein corona-based therapy to treat MSiNP-induced corneal disease, where the corneal damage could be rescued by fetal bovine serum (FBS) treatment.