Anti‐inflammatory Properties of Cerium Oxide Nanoparticles

The valence and oxygen defect properties of cerium oxide nanoparticles (nanoceria) suggest that they may act as auto‐regenerative free radical scavengers. Overproduction of the free radical nitric oxide (NO) by the enzyme inducible nitric oxide synthase (iNOS) has been implicated as a critical mediator of inflammation. NO is correlated with disease activity and contributes to tissue destruction. The ability of nanoceria to scavenge free radicals, or reactive oxygen species (ROS), and inhibit inflammatory mediator production in J774A.1 murine macrophages is investigated. Cells internalize nanoceria, the treatment is nontoxic, and oxidative stress and pro‐inflammatory iNOS protein expression are abated with stimulation. In vivo studies show nanoceria deposition in mouse tissues with no pathogenicity. Taken together, it is suggested that cerium oxide nanoparticles are well tolerated in mice and are incorporated into cellular tissues. Furthermore, nanoceria may have the potential to reduce ROS production in states of inflammation and therefore serve as a novel therapy for chronic inflammation.     

Gold Nanoparticles of Diameter 1.4 nm Trigger Necrosis by Oxidative Stress and Mitochondrial Damage

Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible. AuNPs of diameter 1.4 nm capped with triphenylphosphine monosulfonate (TPPMS), Au1.4MS, are much more cytotoxic than 15‐nm nanoparticles (Au15MS) of similar chemical composition. Here, major cell‐death pathways are studied and it is determined that the cytotoxicity is caused by oxidative stress. Indicators of oxidative stress, reactive oxygen species (ROS), mitochondrial potential and integrity, and mitochondrial substrate reduction are all compromised. Genome‐wide expression profiling using DNA gene arrays indicates robust upregulation of stress‐related genes after 6 and 12 h of incubation with a 2 × IC50 concentration of Au1.4MS but not with Au15MS nanoparticles. The caspase inhibitor Z‐VAD‐fmk does not rescue the cells, which suggests that necrosis, not apoptosis, is the predominant pathway at this concentration. Pretreatment of the nanoparticles with reducing agents/antioxidants N‐acetylcysteine, glutathione, and TPPMS reduces the toxicity of Au1.4MS. AuNPs of similar size but capped with glutathione (Au1.1GSH) likewise do not induce oxidative stress. Besides the size dependency of AuNP toxicity, ligand chemistry is a critical parameter determining the degree of cytotoxicity. AuNP exposure most likely causes oxidative stress that is amplified by mitochondrial damage. Au1.4MS nanoparticle cytotoxicity is associated with oxidative stress, endogenous ROS production, and depletion of the intracellular antioxidant pool.     

Understanding the Antibacterial Mechanism of CuO Nanoparticles: Revealing the Route of Induced Oxidative Stress

To date, there is still a lack of definite knowledge regarding the interaction of CuO nanoparticles with bacteria and the possible permeation of the nanoparticles into bacterial cells. This study was aimed at shedding light on the size‐dependent (from the microscale down to the small nanoscale) antibacterial activity of CuO. The potent antibacterial activity of CuO nanoparticles was found to be due to ROS‐generation by the nanoparticles attached to the bacterial cells, which in turn provoked an enhancement of the intracellular oxidative stress. This paradigm was confirmed by several assays such as lipid peroxidation and reporter strains of oxidative stress. Furthermore, electron microscopy indicated that the small nanoparticles of CuO penetrated the cells. Collectively, the results reported herein may reconcile conflicting concepts in the literature concerning the antibacterial mechanism of CuO nanoparticles, as well as highlight the potential for developing sustainable CuO nanoparticles‐based devices for inhibiting bacterial infections.     

Inorganic Nanoparticles for MRI Contrast Agents

Various inorganic nanoparticles have been used as magnetic resonance imaging (MRI) contrast agents due to their unique properties, such as large surface area and efficient contrasting effect. Since the first use of superparamagnetic iron oxide (SPIO) as a liver contrast agent, nanoparticulate MRI contrast agents have attracted a lot of attention. Magnetic iron oxide nanoparticles have been extensively used as MRI contrast agents due to their ability to shorten T2* relaxation times in the liver, spleen, and bone marrow. More recently, uniform ferrite nanoparticles with high crystallinity have been successfully employed as new T2 MRI contrast agents with improved relaxation properties. Iron oxide nanoparticles functionalized with targeting agents have been used for targeted imaging via the site‐specific accumulation of nanoparticles at the targets of interest. Recently, extensive research has been conducted to develop nanoparticle‐based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle‐based negative T2 contrast agents. In this report, we summarize the recent progress in inorganic nanoparticle‐based MRI contrast agents.     

Emission reduction on ethanol–gasoline blend using cerium oxide nanoparticles as fuel additive

In this study, the effect of ethanol–gasoline blend with cerium oxide nanoparticles as additive on a Tata Nano twin–cylinder SI engine was investigated. In this work, the combustion, performance and emission tests were conducted. The experiment fuels were prepared using 99.9% pure ethanol and gasoline with cerium oxide nanoparticles. The volumetric percentages of ethanol–gasoline blends with cerium oxide nanoparticles additive are in the ratio of E30, E40 and E50. These represent the ratios of ethanol amount in the total blend and the rest of gasoline. Additionally, 100?mg, 150?mg and 200?mg cerium oxide nanoparticles additive are mixed to E30, E40 and E50, respectively. The venture of this investigation was to reformulate the fuel to utilize the cerium oxide nanoparticles with ethanol and gasoline blend to develop the fuel’s performance and to decrease the pollution from the engine. The experimental results expose an increase in brake thermal efficiency for the nanoparticles blends. In the emission test CO, CO₂, HC and NOx are noticeably reduced, and O₂ increased for all the blends. In combustion analyses, the cylinder pressure is higher for nanoparticles blends, when compared to that of the sole fuel.     

Mechanisms of Antibacterial Activity of MgO: Non‐ROS Mediated Toxicity of MgO Nanoparticles Towards Escherichia coli

The toxicity of metal oxide nanomaterials and their antimicrobial activity is attracting increasing attention. Among these materials, MgO is particularly interesting as a low cost, environmentally‐friendly material. The toxicity of MgO, similar to other metal oxide nanomaterials, is commonly attributed to the production of reactive oxygen species (ROS). We investigated the toxicity of three different MgO nanoparticle samples, and clearly demonstrated robust toxicity towards Escherichia coli bacterial cells in the absence of ROS production for two MgO nanoparticle samples. Proteomics data also clearly demonstrate the absence of oxidative stress and indicate that the primary mechanism of cell death is related to the cell membrane damage, which does not appear to be due to lipid peroxidation.     

An Experimental and Computational Approach to the Development of ZnO Nanoparticles that are Safe by Design

Zinc oxide nanoparticles have found wide application due to their unique optoelectronic and photocatalytic characteristics. However, their safety aspects remain of critical concern, prompting the use of physicochemical modifications of pristine ZnO to reduce any potential toxicity. However, the relationships between these modifications and their effects on biology are complex and still relatively unexplored. To address this knowledge gap, a library of 45 types of ZnO nanoparticles with varying particle size, aspect ratio, doping type, doping concentration, and surface coating is synthesized, and their biological effects measured. Three biological assays measuring cell damage or stress are used to study the responses of human umbilical vein endothelial cells (HUVECs) or human hepatocellular liver carcinoma cells (HepG2) to the nanoparticles. These experimental data are used to develop quantitative and predictive computational models linking nanoparticle properties to cell viability, membrane integrity, and oxidative stress. It is found that the concentration of nanoparticles the cells are exposed to, the type of surface coating, the nature and extent of doping, and the aspect ratio of the particles make significant contributions to the cell toxicity of the nanoparticles tested. Our study shows that it is feasible to generate models that could be used to design or optimize nanoparticles with commercially useful properties that are also safe to humans and the environment.     

Ga‐Based Liquid Metal Micro/Nanoparticles: Recent Advances and Applications

Liquid metals are emerging as fluidic inorganic materials in various research fields. Micro‐ and nanoparticles of Ga and its alloys have received particular attention in the last decade due to their non toxicity and accessibility in ambient conditions as well as their interesting chemical, physical, mechanical, and electrical properties. Unique features such as a fluidic nature and self‐passivating oxide skin make Ga‐based liquid metal particles (LMPs) distinguishable from conventional inorganic particles in the context of synthesis and applications. Here, recent advances in the bottom‐up and top‐down synthetic methods of Ga‐based LMPs, their physicochemical properties, and their applications are summarized. Finally, the current status of the LMPs is highlighted and perspectives on future directions are also provided.     

All Roads Lead to the Liver: Metal Nanoparticles and Their Implications for Liver Health

Metal nanoparticles (NPs) are frequently encountered in daily life, and concerns have been raised about their toxicity and safety. Among which, they naturally accumulate in the liver after introduction into the body, independent of the route of administration. Some NPs exhibit intrinsic pharmaceutical effects that are related to their physical parameters, and their inadvertent accumulation in the liver can exert strong effects on liver function and structure. Even as such physiological consequences are often categorically dismissed as toxic and deleterious, there are cell type‐specific and NP‐specific biological responses that elicit distinctive pharmacological consequences that can be harnessed for good. By limiting the scope of discussion to metallic NPs, this work attempts to provide a balanced perspective on their safety in the liver, and discusses both possible therapeutic benefits and potential accidental liver damage arising from their interaction with specific parenchymal and nonparenchymal cell types in the liver.     

Cytotoxicity of nanoparticles

Human exposure to nanoparticles is inevitable as nanoparticles become more widely used and, as a result, nanotoxicology research is now gaining attention. However, while the number of nanoparticle types and applications continues to increase, studies to characterize their effects after exposure and to address their potential toxicity are few in comparison. In the medical field in particular, nanoparticles are being utilized in diagnostic and therapeutic tools to better understand, detect, and treat human diseases. Exposure to nanoparticles for medical purposes involves intentional contact or administration; therefore, understanding the properties of nanoparticles and their effect on the body is crucial before clinical use can occur. This Review presents a summary of the in vitro cytotoxicity data currently available on three classes of nanoparticles. With each of these nanoparticles, different data has been published about their cytotoxicity due to varying experimental conditions as well as differing nanoparticle physiochemical properties. For nanoparticles to move into the clinical arena, it is important that nanotoxicology research uncovers and understands how these multiple factors influence the toxicity of nanoparticles so that their undesirable properties can be avoided.     

The Use of Nanoparticles to Deliver Nitric Oxide to Hepatic Stellate Cells for Treating Liver Fibrosis and Portal Hypertension

Polymeric nanoparticles are designed to transport and deliver nitric oxide (NO) into hepatic stellate cells (HSCs) for the potential treatment of both liver fibrosis and portal hypertension. The nanoparticles, incorporating NO donor molecules (S‐nitrosoglutathione compound), are designed for liver delivery, minimizing systemic delivery of NO. The nanoparticles are decorated with vitamin A to specifically target HSCs. We demonstrate, using in vitro and in vivo experiments, that the targeted nanoparticles are taken up specifically by rat primary HSCs and the human HSC cell line accumulating in the liver. When nanoparticles, coated with vitamin A, release NO in liver cells, we find inhibition of collagen I and α‐smooth muscle actin (α‐SMA), fibrogenic genes associated with activated HSCs expression in primary rat liver and human activated HSCs without any obvious cytotoxic effects. Finally, NO‐releasing nanoparticles targeted with vitamin A not only attenuate endothelin‐1 (ET‐1) which elicites HSC contraction but also acutely alleviates haemodynamic disorders in bile duct‐ligated‐induced portal hypertension evidenced by decreasing portal pressure (≈20%) and unchanging mean arterial pressure. This study clearly shows, for the first time, the potential for HSC targeted nanoparticle delivery of NO as a treatment for liver diseases with proven efficacy for alleviating both liver fibrosis and portal hypertension.     

Cyclodextrin‐Derived Intrinsically Bioactive Nanoparticles for Treatment of Acute and Chronic Inflammatory Diseases

Inflammation is a common cause of many acute and chronic inflammatory diseases. A major limitation of existing anti‐inflammatory therapeutics is that they cannot simultaneously regulate pro‐inflammatory cytokine production, oxidative stress, and recruitment of neutrophils and macrophages. To overcome this limitation, nanoparticles (NPs) with multiple pharmacological activities are synthesized, using a chemically modified cyclic oligosaccharide. The manufacture of this type of bioactive, saccharide material‐based NPs (defined as LCD NP) is straightforward, cost‐effective, and scalable. Functionally, LCD NP effectively inhibits inflammatory response, oxidative stress, and cell migration for both neutrophils and macrophages, two major players of inflammation. Therapeutically, LCD NP shows desirable efficacies for the treatment of acute and chronic inflammatory diseases in mouse models of peritonitis, acute lung injury, and atherosclerosis. Mechanistically, the therapeutic benefits of LCD NP are achieved by inhibiting neutrophil‐mediated inflammatory macrophage recruitment and by preventing subsequent pro‐inflammatory events. In addition, LCD NP shows good safety profile in a mouse model. Thus, LCD NP can serve as an effective anti‐inflammatory nanotherapy for the treatment of inflammatory diseases mainly associated with neutrophil and macrophage infiltration.     

Persistency of Enlarged Autolysosomes Underscores Nanoparticle‐Induced Autophagy in Hepatocytes

The diverse biological effects of nanomaterials form the basis for their applications in biomedicine but also cause safety issues. Induction of autophagy is a cellular response after nanoparticles exposure. It may be beneficial in some circumstances, yet autophagy‐mediated toxicity raises an alarming concern. Previously, it has been reported that upconversion nanoparticles (UCNs) elicit liver damage, with autophagy contributing most of this toxicity. However, the detailed mechanism is unclear. This study reveals persistent presence of enlarged autolysosomes in hepatocytes after exposure to UCNs and SiO₂ nanoparticles both in vitro and in vivo. This phenomenon is due to anomaly in the autophagy termination process named autophagic lysosome reformation (ALR). Phosphatidylinositol 4‐phosphate (PI(4)P) relocates onto autolysosome membrane, which is a key event of ALR. PI(4)P is then converted into phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P₂) by phosphatidylinositol‐4‐phosphate 5‐kinase. Clathrin is subsequently recruited by PI(4,5)P₂ and leads to tubule budding of ALR. Yet it is observed that PI(4)P cannot be converted in nanoparticle‐treated hepatocytes cells. Exogenous supplement of PI(4,5)P₂ suppresses the enlarged autolysosomes in vitro. Abolishment of these enlarged autolysosomes by autophagy inhibitor relieves the hepatotoxicity of UCNs in vivo. The results provide evidence for disrupted ALR in nanoparticle‐treated hepatocytes, suggesting that the termination of nanoparticle‐induced autophagy is of equal importance as the initiation.     

Alkyl‐Capped Silicon Nanocrystals Lack Cytotoxicity and have Enhanced Intracellular Accumulation in Malignant Cells via Cholesterol‐Dependent Endocytosis

Nanocrystals of various inorganic materials are being considered for application in the life sciences as fluorescent labels and for such therapeutic applications as drug delivery or targeted cell destruction. The potential applications of the nanoparticles are critically compromised due to the well‐documented toxicity and lack of understanding about the mechanisms involved in the intracellular internalization. Here intracellular internalization and toxicity of alkyl‐capped silicon nanocrystals in human neoplastic and normal primary cells is reported. The capped nanocrystals lack cytotoxicity, and there is a marked difference in the rate and extent of intracellular accumulation of the nanoparticles between human cancerous and non‐cancerous primary cells, the rate and extent being higher in the malignant cells compared to normal human primary cells. The exposure of the cells to the alkyl‐capped nanocrystals demonstrates no evidence of in vitro cytotoxicity when assessed by cell morphology, apoptosis, and cell viability assays. The internalization of the nanocrystals by Hela and SW1353 cells is almost completely blocked by the pinocytosis inhibitors filipin, cytochalasin B, and actinomycin D. The internalization process is not associated with any surface change in the nanoparticles, as their luminescence spectrum is unaltered upon transport into the cytosol. The observed dramatic difference in the rate and extent of internalization of the nanocrystals between malignant and non‐malignant cells therefore offers potential application in the management of human neoplastic conditions.     

Mass Cytometry and Single‐Cell RNA‐seq Profiling of the Heterogeneity in Human Peripheral Blood Mononuclear Cells Interacting with Silver Nanoparticles

Understanding the interactions between nanoparticles (NPs) and human immune cells is necessary for justifying their utilization in consumer products and biomedical applications. However, conventional assays may be insufficient in describing the complexity and heterogeneity of cell–NP interactions. Herein, mass cytometry and single‐cell RNA‐sequencing (scRNA‐seq) are complementarily used to investigate the heterogeneous interactions between silver nanoparticles (AgNPs) and primary immune cells. Mass cytometry reveals the heterogeneous biodistribution of the positively charged polyethylenimine‐coated AgNPs in various cell types and finds that monocytes and B cells have higher association with the AgNPs than other populations. scRNA‐seq data of these two cell types demonstrate that each type has distinct responses to AgNP treatment: NRF2‐mediated oxidative stress is confined to B cells, whereas monocytes show Fcγ‐mediated phagocytosis. Besides the between‐population heterogeneity, analysis of single‐cell dose–response relationships further reveals within‐population diversity for the B cells and naïve CD4⁺ T cells. Distinct subsets having different levels of cellular responses with respect to their cellular AgNP doses are found. This study demonstrates that the complementary use of mass cytometry and scRNA‐seq is helpful for gaining in‐depth knowledge on the heterogeneous interactions between immune cells and NPs and can be incorporated into future toxicity assessments of nanomaterials.     

Colorimetric biosensing using smart materials

In recent years, colorimetric biosensing has attracted much attention because of its low cost, simplicity, and practicality. Since color changes can be read out by the naked eye, colorimetric biosensing does not require expensive or sophisticated instrumentation and may be applied to field analysis and point-of-care diagnosis. For transformation of the detection events into color changes, a number of smart materials have been developed, including gold nanoparticles, magnetic nanoparticles, cerium oxide nanoparticles, carbon nanotubes, graphene oxide, and conjugated polymers. Here, we focus on recent developments in colorimetric biosensing using these smart materials. Along with introducing the mechanisms of color changes based on different smart materials, we concentrate on the design of biosensing assays and their potential applications in biomedical diagnosis and environmental monitoring.     

In vitro safety toxicology data for evaluation of gold nanoparticles-chronic cytotoxicity, genotoxicity and uptake

Safety and toxic effects of nanoparticles are still largely unexplored due to the multiple aspects that influence their behaviour toward biological systems. Here, we focus the attention on 12 nm spherical gold nanoparticle coated or not with hyaluronic acid compared to its precursor counterpart salt. Results ranging from the effects of a 10-days exposure in an in vitro model with BALB/c 3T3 fibroblast cells show how 12 nm spherical gold nanoparticles are internalized from 3T3 cells by endo-lysosomal pathway by an indirect measurement technique; and how gold nanoparticles, though not being a severe cytotoxicant, induce DNA damage probably through an indirect mechanism due to oxidative stress. While coating them with hyaluronic acid reduces gold nanoparticles cytotoxicity and slows their cell internalization. These results will be of great interest to medicine, since they indicate that gold nanoparticles (with or without coating) are suitable for therapeutic applications due to their tunable cell uptake and low toxicity.     

The Role of Surface Chemistry on the Toxicity of Ag Nanoparticles

The role of surface chemistry on the toxicity of Ag nanoparticles is investigated using Saccharomyces cerevisiae yeast as a platform for evaluation. Combining the shape‐controlled synthesis of Ag nanoparticles with a comprehensive characterization of their physicochemical properties, an understanding is formed of the correlation between the physicochemical parameters of nanoparticles and the inhibition growth of yeast cells upon the introduction of nanoparticles into the cell culture system. Capping agents, surface facets, and sample stability—the three experimental parameters that are inherent from the wet‐chemical synthesis of Ag nanoparticles—have a strong impact on toxicity evaluation. Hence, it is important to characterize surface properties of Ag nanoparticles in the nature of biological media and to understand the role that surface chemistry may interplay to correlate the physicochemical properties of nanoparticles with their biological response upon exposure. This work demonstrates the great importance of surface chemistry in designing experiments for reliable toxicity evaluation and in mitigating the toxicity of Ag nanoparticles for their safe use in future commercialization.     

Rethinking Nano‐TiO2 Safety: Overview of Toxic Effects in Humans and Aquatic Animals

Titanium dioxide nanoparticles (nano‐TiO₂) are widely used in consumer products, raising environmental and health concerns. An overview of the toxic effects of nano‐TiO₂ on human and environmental health is provided. A meta‐analysis is conducted to analyze the toxicity of nano‐TiO₂ to the liver, circulatory system, and DNA in humans. To assess the environmental impacts of nano‐TiO₂, aquatic environments that receive high nano‐TiO₂ inputs are focused on, and the toxicity of nano‐TiO₂ to aquatic organisms is discussed with regard to the present and predicted environmental concentrations. Genotoxicity, damage to membranes, inflammation and oxidative stress emerge as the main mechanisms of nano‐TiO₂ toxicity. Furthermore, nano‐TiO₂ can bind with free radicals and signal molecules, and interfere with the biochemical reactions on plasmalemma. At the higher organizational level, nano‐TiO₂ toxicity is manifested as the negative effects on fitness‐related organismal traits including feeding, reproduction and immunity in aquatic organisms. Bibliometric analysis reveals two major research hot spots including the molecular mechanisms of toxicity of nano‐TiO₂ and the combined effects of nano‐TiO₂ and other environmental factors such as light and pH. The possible measures to reduce the harmful effects of nano‐TiO₂ on humans and non‐target organisms has emerged as an underexplored topic requiring further investigation.