Impact of physicochemical properties on biological effects of lipid nanoparticles: Are they completely safe.

Lipid nanoparticles (LNPs) are promising materials and human-use approved excipients, with manifold applications in biomedicine. Researchers have tended to focus on improving the pharmacological efficiency and organ targeting of LNPs, while paid relatively less attention to the negative aspects created by their specific physicochemical properties. Here, we discuss the impacts of LNPs' physicochemical properties (size, surface hydrophobicity, surface charge, surface modification and lipid composition) on the adsorption-transportation-distribution-clearance processes and bio-nano interactions. In addition, since there is a lack of review emphasizing on toxicological profiles of LNPs, this review outlined immunogenicity, inflammation, hemolytic toxicity, cytotoxicity and genotoxicity induced by LNPs and the underlying mechanisms, with the aim to understand the properties that underlie the biological effects of these materials. This provides a basic strategy that increased efficacy of medical application with minimized side-effects can be achieved by modulating the physicochemical properties of LNPs. Therefore, addressing the effects of physicochemical properties on toxicity induced by LNPs is critical for understanding their environmental and health risks and will help clear the way for LNPs-based drugs to eventually fulfill their promise as a highly effective therapeutic agents for diverse diseases in clinic.

Maternal exposure to sunlight-irradiated graphene oxide induces neurodegeneration-like symptoms in zebrafish offspring through intergenerational translocation and genomic DNA methylation alterations.

The physiochemical properties of graphene oxide may be affected by sunlight irradiation. However, the underlying mechanisms that alter the properties and subsequent intergenerational effects are not sufficiently investigate. Epigenetics is an early sensitive marker for the intergenerational effects of nanomaterial exposure due to the epigenetic memory. In this study, we investigate changes in the physicochemical properties and the intergenerational effects of maternal exposure to simulated sunlight-irradiated polyethyleneimine-functionalized graphene oxide (SL-PEI-GO). Results show that the physicochemical properties of polyethyleneimine-functionalized graphene oxide (PEI-GO) can be altered significantly by the oxidation of carbon atoms with unpaired electrons present in the defects and on the edges of PEI-GO by sunlight. First, the positive charges, sharp edges, defects and disordered structures of SL-PEI-GO make it translocate from maternal zebrafish to offspring, thus catalyzing the production of reactive oxygen species and damaging mitochondria directly. In addition, changes in DNA methylation reduce the expression of protocadherin1a, protocadherin19 and cadherin4, thus destroying cell membrane integrity, cell adhesion and Ca2+ binding. The alteration of DNA methylation induced by maternal exposure activates the Ca2+-CaMKK-brsk2a pathway, which catalyzes the phosphorylation of Tau and eventually results in the appearance of neurodegeneration-like symptoms, including the loss of neurons and neurobehavioral disorders. This study demonstrates that maternal exposure to SL-PEI-GO induces clear neurodegeneration-like symptoms in offspring through both the intergenerational translocation of nanomaterials and differential DNA methylation. These findings may provide new insights into the health risks of nanomaterials altered by nature conditions.

Mitochondria-targeted TPP-MoS2 with dual enzyme activity provides efficient neuroprotection through M1/M2 microglial polarization in an Alzheimer's disease model.

Alzheimer's disease (AD) is one of the most common age-associated brain diseases and is induced by the accumulation of amyloid beta (Aß) and oxidative stress. Many studies have focused on eliminating Aß by nanoparticle affinity; however, nanoparticles are taken up mainly by microglia rather than neurons, leading poor control of AD. Herein, mitochondria-targeted nanozymes known as (3-carboxypropyl)triphenyl-phosphonium bromide-conjugated 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]-functionalized molybdenum disulfide quantum dots (TPP-MoS2 QDs) were designed. TPP-MoS2 QDs mitigate Aß aggregate-mediated neurotoxicity and eliminate Aß aggregates in AD mice by switching microglia from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype. TPP-MoS2 QDs cross the blood-brain barrier, escape from lysosomes, target mitochondria and exhibit the comprehensive activity of a bifunctional nanozyme, thus preventing spontaneous neuroinflammation by regulating the proinflammatory substances interleukin-1ß, interleukin-6 and tumor necrosis factors as well as the anti-inflammatory substance transforming growth factor-ß. In contrast to the low efficacy of eliminating Aß by nanoparticle affinity, the present study provides a new pathway to mitigate AD pathology through mitochondria-targeted nanozymes and M1/M2 microglial polarization.

Graphene Oxide Quantum Dots Reduce Oxidative Stress and Inhibit Neurotoxicity In Vitro and In Vivo through Catalase-Like Activity and Metabolic Regulation.

Both oxidative stress and neurotoxicity are huge challenges to human health, and effective methods and agents for resisting these adverse effects are limited, especially in vivo. It is shown here that, compared to large graphene oxide (GO) nanosheets, GO quantum dots (GOQDs), as nanozymes, efficiently reduce reactive oxygen species (ROS) and H2O2 in 1-methyl-4-phenyl-pyridinium ion (MPP+)-induced PC12 cells. In addition, GOQDs exert neuroprotective effects in a neuronal cell model by decreasing apoptosis and α-synuclein. GOQDs also efficiently diminish ROS, apoptosis, and mitochondrial damage in zebrafish treated with MPP+. Furthermore, GOQDs-pretreated zebrafish shows increased locomotive activity and Nissl bodies in the brain, confirming that GOQDs ameliorate MPP+-induced neurotoxicity, in contrast to GO nanosheets. GOQDs contribute to neurotoxic amelioration by increasing amino acid metabolism, decreasing tricarboxylic acid cycle activity, and reducing steroid biosynthesis, fatty acid biosynthesis, and galactose metabolic pathway activity, which are related to antioxidation and neurotransmission. Meanwhile, H2O2 decomposition and Fenton reactions suggest the catalase-like activity of GOQDs. GOQDs can translocate into zebrafish brains and exert catalase-mimicking activity to resist oxidation in the intracellular environment. Unlike general nanomaterials, biocompatible GOQDs demonstrate their high potential for human health by reducing oxidative stress and inhibiting neurotoxicity.

Characterization and toxicity of nanoscale fragments in wastewater treatment plant effluent.

Much attention has been paid to extracting and isolating specific and well-known nanoparticles (especially for engineered nanomaterials) from complex environmental matrices. However, such research may not provide global information on actual contamination because nanoscale fragments exist as mixtures of various elements and matrices in the real environment. The present work first isolated and characterized nanoscale fragments in effluents from municipal wastewater treatment plants (WWTPs). The nanoscale fragments were found to be composed of 70-85% carbon and low amounts of oxygen, heavy metals and other elements and exhibited nanosheet topographies (approximately 0.87-1.31 nm thickness and 68-187 nm lateral length). Because the isolated nanoscale fragments were mixtures rather than one specific type of nanoparticle, they were present at high concentrations ranging from 0.07 to 0.55 mg/L. It was also found that the accumulation of nanoscale fragments in rice reached 0.59 mg/g under exposure to environmentally relevant concentrations, leading to marked phytotoxicity (e.g., ultrastructural damage to chloroplasts and mitochondria). Metabolic analysis revealed the toxicological mechanisms to be related to disorders of carbohydrate, amino acid and fatty acid metabolism. This study is the first to characterize the properties and analyze the toxicity of nanoscale fragments in the effluents of WWTPs. Given that WWTP effluents containing nanoscale fragments are continuously discharged to the soil, surface water and seas, nanoscale fragment materials deserve considerable attention in future work compared with the few widely studied engineered nanoparticles.

Rice ingestion is a major pathway for human exposure to organophosphate flame retardants (OPFRs) in China.

Although organophosphate flame retardants (OPFRs) have been shown to accumulate in abiotic and biotic environmental compartments, data about OPFRs concentrations in various foods are limited and are none in humans through diets. In this work, the concentrations of 6 typical OPFRs were investigated in 50 rice samples, 75 commonly consumed foods and 45 human hair samples from China. The dietary intakes of OPFRs for adult people via food ingestion were estimated. The concentrations of ΣOPFRs in foods ranged from 0.004ng/g to 287ng/g. OPFRs were detected in 53.3% of the human hair samples. The highest OPFRs concentrations were found in rice and vegetables. Tri(2-chloroethyl)phosphate(TCEP), tris(2-chloroisopropyl)phosphate(TCIPP), and tri(2-ethyltexyl)phosphate(TEHP) were predominant in all food samples. OPFRs concentrations in foods were not significantly affected by the packaging materials. The mean dietary intakes of ΣOPFRs for adult males and females were 539 and 601ng/kg body weight/day, respectively. The greatest contribution to these values is from rice, accounting for approximately 60% of the total intake, particularly from rice protein. Rice ingestion was considered a potential major pathway for human exposure to OPFRs, and regional differences in the levels of OPFRs in foods and dietary differences should be given more attention in the future.

Ultra-trace graphene oxide in a water environment triggers Parkinson's disease-like symptoms and metabolic disturbance in zebrafish larvae.

Over the past decade, the safety of nanomaterials has attracted attention due to their rapid development. The relevant health threat of these materials remains largely unknown, particularly at environmentally or biologically relevant ultra-trace concentrations. To address this, we first found that graphene oxide (GO, a carbon nanomaterial that receives extensive attention across various disciplines) at concentrations of 0.01 µg/L-1 µg/L induced Parkinson's disease-like symptoms in zebrafish larvae. In this model, zebrafish showed a loss of more than 90% of dopamine neurons, a 69-522% increase in Lewy bodies (α-synuclein and ubiquitin) and significantly disturbed locomotive activity. Moreover, it was also shown that GO was able to translocate from the water environment to the brain and localize to the nucleus of the diencephalon, thereby inducing structural and morphological damage in the mitochondria. Cell apoptosis and senescence were triggered via oxidative stress, as shown by the upregulation of caspase 8 and ß-galactosidase. Using metabolomics, we found that the upregulation of amino acid and some fatty acids (e.g. dodecanoic acid, hexadecanoic acid, octadecenoic acid, nonanoic acid, arachidonic acid, eicosanoic acid, propanoic acid and benzenedicarboxylic acid) metabolism and the downregulation of some other fatty acids (e.g. butanoic acid, phthalic acid and docosenoic acid) are linked to these Parkinson's disease-like symptoms. These findings broaden our understanding of nanomaterial safety at ultra-trace concentrations.

Mitigation in Multiple Effects of Graphene Oxide Toxicity in Zebrafish Embryogenesis Driven by Humic Acid.

Graphene oxide (GO) is a widely used carbonaceous nanomaterial. To date, the influence of natural organic matter (NOM) on GO toxicity in aquatic vertebrates has not been reported. During zebrafish embryogenesis, GO induced a significant hatching delay and cardiac edema. The intensive interactions of GO with the chorion induces damage to chorion protuberances, excessive generation of (•)OH, and changes in protein secondary structure. In contrast, humic acid (HA), a ubiquitous form of NOM, significantly relieved the above adverse effects. HA reduced the interactions between GO and the chorion and mitigated chorion damage by regulating the morphology, structures, and surface negative charges of GO. HA also altered the uptake and deposition of GO and decreased the aggregation of GO in embryonic yolk cells and deep layer cells. Furthermore, HA mitigated the mitochondrial damage and oxidative stress induced by GO. This work reveals a feasible antidotal mechanism for GO in the presence of NOM and avoids overestimating the risks of GO in the natural environment.