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Nanoparticles have useful functions due to the characteristics conferred on them by an increase in their specific surface area, and they have already been put into practical use in products in various industrial fields. Although exposure to nanoparticles in daily life is unavoidable for pregnant women, studies that evaluate the toxicity of nanoparticles in pregnant women are lacking. To redress this, we have focused on the placenta and have previously revealed that nanoparticles can show placental toxicity. However, there is still little knowledge regarding the behavior of nanoparticles within placental cells, which would enable us to understand their mode of action. Here, we tried to clarify the intracellular localization of silica nanoparticles in placental cells and how this affects placental toxicity. We analyzed the uptake of silica nanoparticles with a diameter of 10 nm (nSP10) into JEG-3 cells, a human choriocarcinoma cell line. Flow cytometry analysis showed that nSP10 labelled with red fluorescence were taken up into JEG-3 cells, and that pre-treatment with the endocytosis inhibitor cytochalasin D inhibited their uptake, suggesting that nSP10 are taken up into JEG-3 cells by the endocytic pathway. Moreover, confocal microscopy revealed that nSP10 are prominently localized in lysosomes. Staining with LysoTracker showed that nSP10 treatment increased the acidic compartment of JEG-3 cells, suggesting lysosome accumulation and swelling. These results indicate that nSP10 taken into placental cells are transferred to lysosomes and may cause lysosomal dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The therapeutic efficacy of camptothecin (CPT), a potent antitumor alkaloid, is hindered by its hydrophobic nature and instability, limiting its clinical use in treating cutaneous squamous cell carcinoma (SCC). This study introduces a novel nano drug delivery system (NDDS) utilizing functionalized mesoporous silica nanoparticles (FMSNs) for efficient CPT delivery. The FMSNs were loaded with CPT and subsequently coated with chitosan (CS) for enhanced stability and bioadhesion. Importantly, CpG oligodeoxynucleotide (CpG ODN) was attached onto the CS-coated FMSNs to leverage the immunostimulatory properties of CpG ODN, augmenting the chemotherapy's efficacy. The final formulation FMSN-CPT-CS-CpG displayed an average size of 241 nm and PDI of 0.316 with an encapsulation efficiency of 95 %. Comprehensive in vitro and in vivo analyses, including B16F10 cells and DMBA/TPA-induced SCC murine model, demonstrated that the FMSN-CPT-CS-CpG formulation significantly enhanced cytotoxicity against B16F10 cells and induced complete regression in 40 % of the in vivo subjects, surpassing the efficacy of standard CPT and FMSN-CPT treatments. This study highlights the potential of combining chemotherapeutic and immunotherapeutic agents in an NDDS for targeted, efficient skin cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Silica nanoparticles (SNPs) have immense potential in biomedical research, particularly in drug delivery and imaging applications, owing to their stability and minimal interactions with biological entities such as tissues or cells., Results: With synthesized and characterized cyanine-dye-doped fluorescent SNPs (CSNPs) using cyanine 3.5, 5.5, and 7 (Cy3.5, Cy5.5, and Cy7). Through systematic analysis, we discerned variations in the surface charge and fluorescence properties of the nanoparticles contingent on the encapsulated dye-(3-aminopropyl)triethoxysilane conjugate, while their size and shape remained constant. The fluorescence emission spectra exhibited a redshift correlated with increasing dye concentration, which was attributed to cascade energy transfer and self-quenching effects. Additionally, the fluorescence signal intensity showed a linear relationship with the particle concentration, particularly at lower dye equivalents, indicating a robust performance suitable for imaging applications. In vitro assessments revealed negligible cytotoxicity and efficient cellular uptake of the nanoparticles, enabling long-term tracking and imaging. Validation through in vivo imaging in mice underscored the versatility and efficacy of CSNPs, showing single-switching imaging capabilities and linear signal enhancement within subcutaneous tissue environment., Conclusions: This study provides valuable insights for designing fluorescence imaging and optimizing nanoparticle-based applications in biomedical research, with potential implications for targeted drug delivery and in vivo imaging of tissue structures and organs., (© 2024. The Author(s).)

The emergence of various lethal bacterial infections and their adherence to medical devices are major public health concerns. The increased bacterial exposure and titer are accompanied by the inappropriate use of antibiotics that sometimes lead to antibiotic resistance, and therefore, a drug-free antibacterial approach is required. Several nanoparticles (NPs) have been developed as antibacterial and antibiofilm coating agents, which can overcome different drug resistance mechanisms by inhibiting the important processes related to bacterial virulence potential. However, developing safe and biocompatible nanomaterials (NMs) for these applications has remained a major challenge due to their poorly understood mechanism of action. In this work, biogenic silica NPs were modified with glutathione (GSH) to form GSH@SNP (∼80 ± 15 nm) for targeting the bacterial cell surface and biofilm. GSH@SNP was loaded with resveratrol to obtain Res_GSH@SNP (∼124 ± 15 nm) that enhances the antibacterial activity of the NPs against Staphylococcus aureus and Escherichia coli by ∼51 and ∼49%, respectively, compared to GSH@SNP. Res_GSH@SNP is responsible for binding to the bacterial cell surface receptors that interrupt the cell membrane potential, leading to reactive oxygen species (ROS) generation, membrane disruption, and DNA damage and eventually resulting in antibacterial activity. Moreover, the antibiofilm activity of Res_GSH@SNP has been found to result from the interaction of the NPs with the abundant carbohydrates present on the biofilm surface. To check the practical utility of Res_GSH@SNP, these were further evaluated as an antibacterial and antibiofilm coating agent for urinary catheters and were found to be effective even after multiple washes. Res_GSH@SNP has been found to exhibit ∼80 ± 1.4% cytocompatibility toward fibroblast NIH-3T3 cells. Overall, this study is expected to pave the way for the development of biocompatible NP-based coating agents for medical devices.

In recent years, the use of nanotechnology-based methods has become widespread in the treatment of ocular diseases. Silica nanoparticles (SiO 2 NPs) are most common used NPs in medical field due to their physicochemical properties. SiO 2 NPs can easily cross biological membranes and interact with basic biological structures, causing structural and functional changes in cells. In this study, it was aimed to investigate the dose dependent effect of SiO 2 NPs on retinal pigment epithelium (RPE) in vitro using electrobiophysical, biochemical and histological methods. A commercially purchased human RPE (hARPE-19) cell line was used in this study. Cells were divided into four groups as control, 50 μg/mL SiO 2 , 100 μg/mL SiO 2 and 150 μg/mL SiO 2 groups. Cell index, apoptotic activity, cell cycle and oxidative stress markers were measured in all groups. Findings in the present study showed that SiO 2 nanoparticles reduced cell proliferation, increased oxidative stress, apoptosis and arrest in the G 0 /G 1 phase of the cell cycle as dose dependent manner in ARPE-19 cells. In conclusion, SiO 2 exposure can induce cytotoxic effects in RPE cell line. The results of this study provide clues that exposure to SiO 2 nanoparticles may impair visual function and reduce quality of life. However, further studies are needed in this regard., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The relationship between environmental exposure to silica nanoparticles (SiNPs) and adverse cardiac outcomes has received more attention. Our recent work has revealed a size-dependent impact of the intratracheal instilled SiNPs on cardiac health of ApoE -/- mice using nanoscale SiNPs-60 and submicro-sized SiNPs-300, but the underlying mechanism of action still remains unclear. Hence, we identified proteins and protein networks perturbed by SiNPs in myocardial tissues of ApoE -/- mice by using LC-MS/MS-based quantitative proteomics. A set of 435 differentially expressed proteins (DEPs) were screened in response to SiNPs, which mainly enriched in the mitochondria and functioned in cell metabolism, biosynthesis and signal transduction. KEGG analysis showed that DEPs were significantly associated with oxidative phosphorylation and cardiomyopathy. The protein-protein interaction (PPI) network revealed 9 DEPs (e.g., Ndufs1, Ndufv1, Cox4i1) as potential biomarkers of SiNPs-induced myocardial toxicity. Of note, all the 9 candidate proteins were subunits of mitochondria respiratory chain complex, and their expressions were dependent on particle size, which were remarkably down-regulated by SiNPs-60 but not by SiNPs-300. More importantly, the correlation analysis verified the 9 dysregulated mitochondria complex protein subunits strongly correlated to the biochemical and functional indexes of cardiac injury in response to SiNPs. In conclusion, our study firstly provided significant proteomic insights into the potential molecular mechanisms underlying SiNPs-elicited cardiotoxicity, with the dysregulated mitochondrial complex subunits as core regulatory molecules. Overall, our study would provide the scientific basis for the molecular actions and mechanisms of toxicity induced by SiNPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Understanding the underlying interactions of nanoparticles (NPs) with cells is crucial to the nanotoxicological research. Evidences suggested lysosomes as a vital target upon the accumulation of internalized NPs, and lysosomal damage and autophagy dysfunction are emerging molecular mechanisms for NPs-elicited toxicity. Nevertheless, the interaction with lysosomes, ensuing adverse effects and the underlying mechanisms are still largely obscure, especially in NPs-induced vascular toxicity. In this study, silica nanoparticles (SiNPs) were utilized to explore the adverse effects on lysosome in vascular endothelial cells by using in vitro cultured human endothelial cells (HUVECs), and in-depth investigated the mechanisms involved. Consequently, the internalized SiNPs accumulated explicitly in the lysosomes, and caused lysosomal dysfunction, which were prominent on the increased lysosomal membrane permeability, decline in lysosomal quantity, destruction of acidic environment of lysosome, and also disruption of lysosomal enzymes activities, resulting in autophagy flux blockage and autophagy dysfunction. More importantly, mechanistic results revealed the SiNPs-caused lysosomal impairments and resultant autophagy dysfunction could promote oxidative stress, DNA damage and the eventual cell apoptosis activated by ROS/PARP1/AIF signaling pathway. These findings improved the understanding of SiNPs-induced vascular injury, and may provide novel information and warnings for SiNPs applications in the fields of nanomedicine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nanoparticles (NPs) can make their way to the brain and cause in situ damage, which is a concern for nanomaterial application and airborne particulate matter exposure. Our recent study indicated that respiratory exposure to silica nanoparticles (SiO 2 NPs) caused unexpected cardiovascular toxic effects. However, the toxicities of SiO 2 NPs in other organs have warranted further investigation. To confirm the accumulation of SiO 2 NPs in the brain, we introduced SiO 2 NPs with different diameters into mice via intranasal instillation (INI) and intravenous injection (IVI) in parallel. We found that SiO 2 NPs may target the brain through both olfactory and systemic routes, but the size of SiO 2 NPs and delivery routes both significantly affected their brain accumulation. Surprisingly, while equivalent SiO 2 NPs were found in the brain regions, brain lesions were distinctly much higher in INI than in the IVI group. Mechanistically, we showed that SiO 2 NPs introduced via INI induced brain apoptosis and autophagy, while the SiO 2 NPs introduced via IVI only induced autophagy in the brain.

This article describes the preparation and identification of SiO2@Glu/Si(OEt)2(CH2)3N=Mo[Mo5O18] as a new bifunctional acid-base catalyst (both acidic and basic Lewis sites). Aminopropyltriethoxysilane was first reacted with hexamolybdate anions and then treated with glucose to prepare Glu/Si(OEt)2(CH2)3N=Mo[Mo5O18]. Nano-silica was then modified by the prepared glucose/molybdate complex to obtain SiO2@Glu/Si(OEt)2(CH2)3N=Mo[Mo5O18]. The developed catalyst was characterized by FT-IR, EDX, XRD, FE-SEM and TGA analyzes. Its catalytic efficiency was investigated for the preparation of pyrano[2,3-d]pyrimidine derivatives by the reaction between various aldehydes, malononitrile and barbituric acid. The desired products were prepared in the presence of 0.004 g of the prepared catalyst in high to excellent yields.

The rapid development of gene therapy and genome editing techniques brings up an urgent need to develop safe and efficient nanoplatforms for nucleic acids and CRISPR genome editors. Herein we report a stimulus-responsive silica nanoparticle (SNP) capable of encapsulating biomacromolecules in their active forms with a high loading content and loading efficiency as well as a well-controlled nanoparticle size (~50 nm). A disulfide crosslinker was integrated into the silica network, endowing SNP with glutathione (GSH)-responsive cargo release capability when internalized by target cells. An imidazole-containing component was incorporated into the SNP to enhance the endosomal escape capability. The SNP can deliver various cargos, including nucleic acids (e.g., DNA and mRNA) and CRISPR genome editors (e.g., Cas9/sgRNA ribonucleoprotein (RNP), and RNP with donor DNA) with excellent efficiency and biocompatibility. The SNP surface can be PEGylated and functionalized with different targeting ligands. In vivo studies showed that subretinally injected SNP conjugated with all-trans-retinoic acid (ATRA) and intravenously injected SNP conjugated with GalNAc can effectively deliver mRNA and RNP to murine retinal pigment epithelium (RPE) cells and liver cells, respectively, leading to efficient genome editing. Overall, the SNP is a promising nanoplatform for various applications including gene therapy and genome editing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Quantities of researches have demonstrated silica nanoparticles (SiNPs) exposure inevitably induced damage to respiratory system, nonetheless, knowledge of its toxicological behavior and metabolic interactions with the cellular machinery that determines the potentially deleterious outcomes are limited and poorly elucidated. Here, the metabolic responses of lung bronchial epithelial cells (BEAS-2B) under SiNPs exposure were investigated using ultra performance liquid chromatography-mass spectrum (UPLC-MS)-based metabolomics research. Results revealed that even with low cytotoxicity, SiNPs disturbed global metabolism. Five metabolic pathways were significantly perturbed, in particular, oxidative stress- and mitochondrial dysfunction-related GSH metabolism and pantothenate and coenzyme A (CoA) biosynthesis, where the identified metabolites glutathione (GSH), glycine, beta-alanine, cysteine, cysteinyl-glycine and pantothenic acid were included. In support of the metabolomics profiling, SiNPs caused abnormality in mitochondrial structure and mitochondrial dysfunction, as evidenced by the inhibition of cellular respiration and ATP production. Moreover, SiNPs triggered oxidative stress as confirmed by the dose-dependent ROS generation, down-regulated nuclear factor erythroid 2-related factor 2 (NRF2) signaling, together with GSH depletion in SiNPs-treated BEAS-2B cells. Oxidative DNA damage and cell membrane dis-integrity were also detected in response to SiNPs exposure, which was correspondingly in agreed with the elevated 8-hydroxyguanosine (8-OHdG) and decreased phospholipids screened through metabolic analysis. Thereby, we successfully used the metabolomics approaches to manifest SiNPs-elicited toxicity through oxidative stress, mitochondrial dysfunction, DNA damage and rupture of membrane integrity in BEAS-2B cells. Overall, our study provided novel insights into the mechanism underlying SiNPs-induced pulmonary toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: As the application of silica nanomaterials continues to expand, increasing chances of its exposure to the human body and potential harm are anticipated. Although the toxicity of silica nanomaterials is assumed to be affected by their physio-chemical properties, including size and surface functionalization, its molecular mechanisms remain unclear. We hypothesized that analysis of intracellular localization of the particles and subsequent intracellular signaling could reveal a novel determinant of inflammatory response against silica particles with different physico-chemical properties., Results: We employed a murine intratracheal instillation model of amorphous silica nanoparticles (NPs) exposure to compare their in vivo toxicities in the respiratory system. Pristine silica-NPs of 50 nm diameters (50 nm-plain) induced airway-centered lung injury with marked neutrophilic infiltration. By contrast, instillation of pristine silica particles of a larger diameter (3 μm; 3 μm-plain) significantly reduced the severity of lung injury and neutrophilic infiltration, possibly through attenuated induction of neutrophil chemotactic chemokines including MIP2. Ex vivo analysis of alveolar macrophages as well as in vitro assessment using RAW264.7 cells revealed a remarkably lower cellular uptake of 3 μm-plain particles compared with 50 nm-plain, which is assumed to be the underlying mechanism of attenuated immune response. The severity of lung injury and neutrophilic infiltration was also significantly reduced after intratracheal instillation of silica NPs with an amine surface modification (50 nm-NH 2 ) when compared with 50 nm-plain. Despite unchanged efficacy in cellular uptake, treatment with 50 nm-NH 2 induced a significantly attenuated immune response in RAW264.7 cells. Assessment of intracellular redox signaling revealed increased reactive oxygen species (ROS) in endosomal compartments of RAW264.7 cells treated with 50 nm-plain when compared with vehicle-treated control. In contrast, augmentation of endosomal ROS signals in cells treated with 50 nm-NH 2 was significantly lower. Moreover, selective inhibition of NADPH oxidase 2 (NOX2) was sufficient to inhibit endosomal ROS bursts and induction of chemokine expressions in cells treated with silica NPs, suggesting the central role of endosomal ROS generated by NOX2 in the regulation of the inflammatory response in macrophages that endocytosed silica NPs., Conclusions: Our murine model suggested that the pulmonary toxicity of silica NPs depended on their physico-chemical properties through distinct mechanisms. Cellular uptake of larger particles by macrophages decreased, while surface amine modification modulated endosomal ROS signaling via NOX2, both of which are assumed to be involved in mitigating immune response in macrophages and resulting lung injury.

Multidrug resistance (MDR) of chemotherapy is one of the significant concerns in cancer therapy. Here in our study, cisplatin (DDP) and oleanolic acid (OA) were co-loaded in mesoporous silica nanoparticles (Nsi) to construct DDP/OA-Nsi and solve the DDP-resistance in lung cancer therapy. The cytotoxicity and apoptosis assays demonstrated that in DDP-resistant A549/DDP cells, the cytotoxicity of DDP/OA-Nsi was significantly higher than that of free DDP or DDP single delivery system (DDP-Nsi). The intracellular drug accumulation study revealed that the intracellular DDP concentration in the DDP/OA-Nsi group was also higher than that in free DDP and DDP-Nsi groups. In the A549/DDP xenograft tumor model, DDP/OA-Nsi showed the best anticancer effect. In summary, DDP/OA-Nsi was a promising drug delivery system to solve MDR in lung cancer therapy., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

A high-performance interdigitated electrode (IDE) biosensing surface was reported here by utilizing self-assembled silica nanoparticle (SiNP). The modified surface was used to evaluate the complementation of hairpin forming region from Mitoxantrone resistance gene 7 (MXR7; liver cancer-related short gene). The conjugated SiNPs on 3-aminopropyl triethoxysilane functionalization were captured with probe sequence on IDE biosensing surface. The physical and chemically modified surface was used to quantify MXR7 and an increment in the current response upon complementation was noticed. Limit of target DNA detection was calculated (1-10 fM) and this label-free detection is at the comparable level to the fluorescent-based sensing. A linear regression was calculated [y = 0.243x - 0.0773; R² = 0.9336] and the sensitivity was 1 fM on the linear range of 1 fM to 10 pM. With the strong attachment of capture DNA on IDE through SiNP, the surface clearly discriminates the specificity (complementary) versus nonspecificity (complete-, single-, and triple-mismatched sequences). This detection strategy helps to determine liver cancer progression and the similar strategy can be followed for other gene sequence complementation., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)

Extensive application of nanomaterials has dramatically increased the risk of silica nanoparticle (SiNP, SiO 2 ) exposure, yet their biological effect on reproduction has not been fully elucidated. By tracking the uterine biodistribution of SiNP in pregnant mice, this study was conducted to evaluate the biological effect of SiNP on reproduction. First, SiNP was conjugated with FITC, and then the FITC-SiNP was administrated to trophoblast (100 µg/mL, 24 h) in vitro and pregnant mice (0.25 mg/mouse, 2-24 h) in vivo. It was found that the FITC-SiNP was internalized by trophoblast and deposited in the uterus. The internalization of SiNP caused trophoblast dysfunction and apoptosis, while SiNP accumulation in the uterus induced diffuse inflammatory infiltration. The genome-wide alteration of gene expression was studied by high throughput sequencing analysis, where 75 genes were found to be dysregulated after SiNP exposure, among which ACOT2, SCD1, and CPT1A were demonstrated to regulate the biosynthesis of unsaturated fatty acids. Moreover, the suppression of unsaturated fatty acids caused mitochondrial overload of long-chain fatty acyl-CoA (LACoA), which further induced both trophoblast apoptosis and endometrial inflammation. In conclusion, the successful conjugation of FITC onto SiNP facilitated the tracking of SiNP in vitro and in vivo, while exposure to FITC-SiNP induced uterine metabolic disorder, which was regulated by the ACOT/CPT1A/SCD1 axis through the biosynthesis of unsaturated fatty acids signaling pathway.

Enzymes are biological catalysts that have many potential industrial and biomedical applications. However, the widespread use of enzymes in the industry has been limited by their instability and poor recovery. In biomedical applications, systemic administration of enzymes has faced two main challenges: limited bioactivity mostly due to rapid degradation by proteases and immunogenic activity, since most enzymes are from nonhuman sources. Herein, we propose a robust enzyme-encapsulation strategy to mitigate these limitations. Catalase (CAT) was encapsulated in nanoporous silica nanoparticles (CAT-SiNPs) by first chemically modifying the enzyme surface with a silica precursor, followed by silica growth and finally poly(ethylene glycol) (PEG) conjugation. The formulation was carried out in mild aqueous conditions and yielded nanoparticles (NPs) with a mean diameter of 230 ± 10 nm and a concentration of 1.3 ± 0.8 × 10 12 NPs/mL. CAT-SiNPs demonstrated high enzyme activity, optimal protection from proteolysis by proteinase K and trypsin, and excellent stability over time. In addition, a new electrochemical assay was developed to measure CAT activity in a rapid, simple, and accurate manner without interference from chromophore usually present in biological samples. Concentrations of 2.5 × 10 10 to 80 × 10 10 CAT-SiNPs/mL not only proved to be nontoxic in cell cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay but also conferred cell protection when cells were exposed to 1 mM hydrogen peroxide (H 2 O 2 ). Finally, the ability of CAT-SiNPs to release oxygen (O 2 ) when exposed to H 2 O 2 was demonstrated in vivo using a rat model. Following the direct injection of CAT-SiNPs in the left kidney, partial pressure of oxygen (pO 2 ) increased by more than 30 mmHg compared to the contralateral control kidney during the systemic infusion of safe levels of H 2 O 2 . This pilot study highlights the potential of CAT-SiNPs to generate O 2 to relieve hypoxia in tissues and potentially sensitize tumors against radiation therapy.

Nanoparticles, i.e., particles with a diameter of ≤100 nm regardless of their composing material, are added to various foods as moisturizers, coloring agents, and preservatives. Silicon dioxide (SiO 2 , silica) nanoparticles in particular are widely used as food additives. However, the influence of SiO 2 nanoparticle oral consumption on intestinal homeostasis remains unclear. The daily intake of 10-nm-sized SiO 2 nanoparticles exacerbates dextran sulfate sodium (DSS)-induced colitis, whereas the daily intake of 30-nm-sized SiO 2 nanoparticles has no influence on intestinal inflammation. The exacerbation of colitis induced by consuming 10-nm-sized SiO 2 nanoparticles was abolished in mice deficient in apoptosis-associated speck-like protein containing a CARD (ASC). Our study indicates that the oral intake of small SiO 2 nanoparticles poses a risk for worsening intestinal inflammation through activation of the ASC inflammasome., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Electrospinning has been widely used to fabricate polymer fibrous scaffolds for bone tissue engineering because of their highly porous structures. In order to improve the biocompatibility of polymer scaffolds, some nano particles have been introduced into electrospun fibres. For example, silica nanoparticles (SiNPs), with high surface area and good biocompatibility, have been used for bone tissue engineering for better bone cell attachment. In this work, porous poly(L-lactic acid) (PLLA) fibrous membrane with high surface area was fabricated by electrospinning and post-treatment process. The membrane can serve as substrates of SiNPs for bone tissue engineering. Dopamine (DOP) was applied to modify the surface of PLLA fibres, which improved the coating strength of SiNPs on PLLA fibres. SiNP coating significantly improved the mechanical properties and hydrophilicity of PLLA/DOP/SiNP composite membranes. As a result of SiNPs coating, PLLA/DOP/SiNP membrane exhibited better cellular biocompatibility, more cell attachment and proliferation. These results demonstrate that porous PLLA/DOP/SiNP composite membrane with high surface area has high potential for periosteum in the field of bone regeneration applications., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 I K1 channels. SiNP-100 increased the action potential amplitude (APA) and the I Na current density, but SiNP-20 decreased APA and I Na density. SiNP-100 prolonged the action potential duration (APD) and decreased the I to current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased I to 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 I Na and I to channels and Ca 2+ homeostasis but not I K1 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., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Liu et al.)

Catechol-based bioadhesives generate hydrogen peroxide (H 2 O 2 ) as a byproduct during the curing process. H 2 O 2 can have both beneficial and deleterious effects on biological systems depending on its concentration. To control the amount of H 2 O 2 released from catechol-containing polyethylene glycol-based adhesive (PEG-DA), adhesive was formulated with silica nanoparticles (SiNP) prepared with increased porosity and acid treatment to increase Si-OH surface content. These SiNP demonstrated increased surface area, which promoted interaction with catechol and resulted in increased cure rate, bulk mechanical properties and adhesive properties of PEG-DA. Most importantly, SiNP demonstrated a 50% reduction in the released H 2 O 2 while improving the cell viability and proliferation of three primary cell types, including rat dermal fibroblasts, human epidermal keratinocytes, and human tenocytes. Additionally, SiNP degraded into soluble Si, which also contributed to increased cell proliferation. Incorporation of porous and acid-treated SiNP can be a useful approach to simultaneously modulate the concentration of H 2 O 2 while increasing the adhesive performance of catechol-based adhesives.

Herein, we have reported a cost-effective method of synthesizing highly efficient silica nanomaterial from rice husks for its application as a chemotherapeutic agent. Silica particle with two different sizes ~20 nm and ~40 nm were achieved from silica precursor obtained from rice husk. 5-Fluorouracil was functionalized onto the surface of silica nanoparticles by direct conjugation and chitosan mediated conjugation. Particle size analysis, zeta potential and functional analyzes were performed in systematic methodology to confirm chitosan coating and 5-Fluorouracil conjugation on silica nanoparticles. The drug loading percentage with respect to the particle size shows that ~20 nm particles have higher loading capacity. The chitosan mediated conjugation of drug shows sustained release in acidic pH and hence suitable for cancer cell-targeted delivery. The in vitro cell culture studies performed on MC3T3 fibroblast cell lines, MCF-7 and A549 cancer cell lines depicts that, compared to direct conjugation of 5-Fluorouracil, chitosan mediated drug conjugation on the surface of silica nanoparticles shows lesser toxic to fibroblast cell lines and higher toxicity towards cancer cell lines. The results of this toxicity were also confirmed from the nucleic acid spectral signature of Raman spectra treated with drug conjugated silica nanoparticles., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The potential to impart surfaces with specific lignin-like properties (i.e. resistance to microbes) remains relatively unexplored due to the lack of well-defined lignin-derived small molecules and corresponding surface functionalization strategies. Here, allyl-modified guaiacyl β-O-4 eugenol (G-eug) lignin-derived dimer is synthesized and attached to mesoporous silica nanoparticles (MSNPs) via click chemistry. The ability of G-eug lignin-dimer functionalized particles to interact with and disrupt synthetic lipid bilayers is compared to that of eugenol, a known natural antimicrobial. Spherical MSNPs (∼150 nm diameter with 4.5 nm pores) were synthesized using surfactant templating. Post-synthesis thiol (SH) attachment was performed using (3-mercaptopropyl) trimethoxysilane and quantified by Ellman's test. The resultant SH-MSNPs were conjugated with the G-eug dimers or eugenol by a thiol-ene reaction under ultraviolet light in the presence of a photo initiator. From thermogravimetric analysis (TGA), attachment densities of approximately 0.22 mmol eugenol/g particle and 0.13 mmol G-eug dimer/g particle were achieved. The interaction of the functionalized MSNPs with a phospholipid bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (representing model cell membranes) supported on gold surface was measured using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). Eugenol-grafted MSNPs in PBS (up to 1 mg/mL) associated with the bilayer and increased the mass adsorbed on the QCM-D sensor. In contrast, MSNPs functionalized with G-eug dimer show qualitatively different behavior, with more uptake and evidence of bilayer disruption at and above a particle concentration of 0.5 mg/mL. These results suggest that bio-inspired materials with conjugated lignin-derived small molecules can serve as a platform for novel antimicrobial coatings and therapeutic carriers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Most nanoparticles (NPs) reportedly block autophagic flux, thereby upregulating p62/SQSTM1 through degradation inhibition. p62 also acts as a multifunctional scaffold protein with multiple domains, and is involved in various cellular processes. However, the autophagy substrate-independent role of p62 and its regulation at the transcriptional level upon NPs exposure remain unclear., Results: In this work, we exposed BEAS-2b cells and mice to silica nanoparticles (SiNPs), and found that SiNPs increased p62 protein levels in vivo and vitro. Then, we further explored the role and mechanism of SiNPs-stimulated p62 in vitro, and found that p62 degradation was inhibited due to autophagic flux blockade. Mechanistically, SiNPs blocked autophagic flux through impairment of lysosomal capacity rather than defective autophagosome fusion with lysosomes. Moreover, SiNPs stimulated translocation of NF-E2-related factor 2 (Nrf2) to the nucleus from the cytoplasm, which upregulated p62 transcriptional activation through direct binding of Nrf2 to the p62 promoter. Nrf2 siRNA dramatically reduced both the mRNA and protein levels of p62. These two mechanisms led to p62 protein accumulation, thus increasing interleukin (IL)-1 and IL-6 expression. SiNPs activated nuclear factor kappa B (NF-κB), and this effect could be alleviated by p62 knockdown., Conclusion: SiNPs caused accumulation of p62 through both pre- and post-translational mechanisms, resulting in airway inflammation. These findings improve our understanding of SiNP-induced pulmonary damage and the molecular targets available to mitigate it.

Silica dioxide nanoparticles (SiONPs) are mainly used in the rubber industry; however, they are a major air pollutant in Asia. Thus, extensive research on this issue is required. In this study, we investigated the effects of SiONPs on asthma aggravation and elucidated the underlying mechanism using ovalbumin (OVA)-induced asthmatic mice model and in NCI-H292 cells. Mice exposed to SiONPs showed markedly increased Penh values, inflammatory cell counts, and inflammatory cytokine levels compared to OVA-induced asthmatic mice. Exposure to SiONPs also induced additional airway inflammation and mucus secretion with increases in protein expression levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and interleukin (IL)-1β compared to those in OVA-induced asthmatic mice. Treatment of SiONPs in NCI-H292 cells also significantly increased mRNA expression levels of inflammatory cytokines accompanied with elevation in the levels of TXNIP, NLRP3 inflammasome, and IL-1β proteins in a concentration-dependent manner. Taken together, exposure to SiONPs aggravated asthma development, which is closely related to inflammasome activation. Our results provide useful information about the toxicological effects of SiONPs on asthma exacerbation and suggest the need to avoid SiONP exposure especially in individuals with respiratory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo., Methods: The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques., Results: In vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentration-dependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca 2+ release activated Ca 2+ (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7-35 mg/kg), particle size, and exposure time (4-72 h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo., Conclusions: SiNPs, administrated in vivo, induced multiple organ injuries, including endothelial damage, intravascular coagulation, and secondary inflammation. The injuries are likely caused by upstream Ca 2+ -ROS signaling and downstream VE-cadherin phosphorylation and destruction and F-actin remodeling. These changes led to endothelial barrier disruption and triggering of the contact coagulation pathway.

The molecular mechanism by which silica nanoparticles (SiNPs) cause cellular apoptosis in the respiratory system is unclear. Silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent deacetylase, mediates the pulmonary damage associated with several environmental stimuli. However, the SIRT1 response to SiNP exposure and its role in SiNP-triggered pulmonary toxicity remains unknown. Here, SiNPs were found to downregulate nuclear rather than cytosolic SIRT1 protein levels in human bronchial epithelial cells (BEAS-2b). They did not affect SIRT1 gene expression but accelerated SIRT1 protein degradation via c-Jun N-terminal kinase (JNK) activation. SiNP-mediated SIRT1 suppression markedly increased tumour protein 53 (p53) acetylation and cytoplasmic localisation, leading to the release of cytochrome c from mitochondria to the cytosol. SIRT1 overexpression dramatically decreased p53 acetylation and its cytoplasmic localisation, and this was accompanied by attenuated apoptosis in SiNP-exposed cells. Finally, SiNPs suppressed SIRT1 and stimulated apoptosis in the lung tissues of mice. In summary, SiNPs downregulate nuclear SIRT1 via JNK activation-mediated protein degradation, which leads to apoptosis via p53 acetylation and cytoplasmic localisation. These findings improve our understanding of SiNP-induced pulmonary damage and molecular targets to antagonise it., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Making a nanoparticle (NP) approach and interact with a plasma membrane (PM) through the receptor-ligand interaction is key for applications like targeted drug delivery, cellular imaging, and theranostics. In this paper, we show that the van der Waals (vdW) interactions dominate the electrostatics ensuring that a gold NP approached the PM more spontaneously as compared to a silica NP. The negative σ (charge density) of a PM induces a negative electrostatic potential at the surface of the approaching gold NP and the silica NP; however, there is very little difference between these induced values due to a small electric double layer at the physiological salt concentration (c ∞ ). Hence there is very little difference in the electrostatic repulsion between the two cases, while the PM-NP vdW attraction is much more for the gold NP as a result of a larger Hamaker constant. Therefore, in comparison to the gold NP, the silica NP would (a) undergo a promotion of the specific adhesion and a prevention of the non-specific adhesion simultaneously for a larger σ - c ∞ phase space including the physiological conditions, (b) necessitate a larger length of the ligands to trigger spontaneous receptor-ligand interactions, and (c) require a larger driving force for force-driven receptor-ligand interactions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Soil acidity (and associated Al toxicity) is a major factor limiting crop production worldwide and threatening global food security. Electrostatic layer-by-layer (LBL) self-assembly provides a convenient and versatile method to form an extracellular silica nanocoat, which possess the ability to protect cell from the damage of physical stress or toxic substances. In this work, we have tested a hypothesis that extracellular silica nanocoat formed by LBL self-assembly will protect root border cells (RBCs) and enhance their resistance to Al toxicity., Results: Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) were used to compare the properties of RBCs surface coated with nanoshells with those that were exposed to Al without coating. The accumulation of Al, reactive oxygen species (ROS) levels, and the activity of mitochondria were detected by a laser-scanning confocal microscopy. We found that a crystal-like layer of silica nanoparticles on the surface of RBCs functions as an extracellular Al-proof coat by immobilizing Al in the apoplast and preventing its accumulation in the cytosol. The silica nanoshells on the RBCs had a positive impact on maintaining the integrity of the plasma and mitochondrial membranes, preventing ROS burst and ensuring higher mitochondria activity and cell viability under Al toxicity., Conclusions: The study provides evidence that silica nanoshells confers RBCs Al resistance by restraining of Al in the silica-coat, suggesting that this method can be used an efficient tool to prevent multibillion-dollar losses caused by Al toxicity to agricultural crop production.

The adverse effects of SiO 2 NPs on the biological systems like nervous system have not been well explored. This study aimed to evaluate the toxicity of SiO 2 NPs on the nervous system in vitro. Therefore, human tau protein and neuroblastoma cell line (SH-SY5Y) were used as targets. In this study we examined the side effects of SiO 2 NPs on tau protein structure using several techniques including CD, ANS fluorescence, UV-vis (360 nm), Congo red absorbance, TEM, and molecular dynamic. Also, the cytotoxicity effects of SiO 2 NPs against SH-SY5Y cell line were evaluated using MTT, ROS and apoptotic assays. Spectroscopic and molecular dynamic investigations indicated that natively unfolded structure of tau in the presence of SiO 2 NPs experienced a partially folded and amorphous aggregated structure. Cellular assay demonstrated that SiO 2 NPs exerted cytotoxic effect on SH-SY5Y cells through ROS accumulation and induction of apoptosis. Overall, these findings proved that SiO 2 NPs could induce adverse effects on tau structure and SH-SY5Y cell integrity. Moreover, further studies are required to elucidate the molecular mechanism of SiO 2 NPs-induced side effects in vivo., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Silica nanoparticles are widely used platform materials for the immobilization of proteins to realize applications in biomedicine and biotechnology. We here report on the use of a highly delicate protein for the systematic evaluation of routes for the surface modification of multifunctional silica nanoparticles. To investigate how surface immobilization methods affect the functionality of surface-bound proteins, we constructed a novel fusion protein, dubbed FlipHOB, that combines the glucose sensor protein FLIP with a variant of the commercially-available self-ligating Halo-tag. As indicated by the spectroscopic properties and sensing capabilities of FlipHOB, the oriented immobilization of this protein through its HOB tag domain or DNA-directed immobilization were superior over the non-directional statistical immobilization via glutardialdehyde-mediated cross-coupling. Immobilization through double-stranded DNA bridges also allows for the triggered disassembly of FlipHOB nanosensors and the controlled recovery of the sensor protein. We demonstrate that the nanosensors are functional in in vitro settings and can be used for imaging in vivo. We believe that our results show generic strategies and provide essential guidelines for the development of protein-based nanoparticle sensors for applications in the life sciences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

With biocompatibility, biodegradability, and high functionality, silica nanoparticles (SNPs) have been widely investigated for various biomedical applications. However, lack of optical fluorescence has limited the application of SNPs as a degradable imaging agent. Here, we hydrothermally synthesized fluorescent SNPs by artificially generating optically active defect centers using tetraethyl orthosilicate and (3-aminopropyl)trimethoxysilane. The synthesized SNPs demonstrated strong blue photoluminescence originating from the dioxasilyrane (=Si(O 2 )) and silylene (=Si:) defect centers with the aid of aminopropyl groups. Furthermore, phosphorescence was observed at 459 nm, indicating the presence of silylene in SNPs. Finally, these SNPs have been successfully utilized as a fluorescent probe for bioimaging of normal, cancer, and macrophage cells.

Selective and sensitive detection of specific molecules in a solution containing diverse coexisting molecules is important in many biomedical and environmental applications, including diagnostics and pollutant detection. Here, a nanofluidic biosensor is developed to detect specific target molecules (e.g., toxin proteins) in the presence of nontarget molecules by bonding a patterned model cell membrane and a silicone elastomer (polydimethylsiloxane: PDMS) sheet using surface-modified silica nanoparticles as the adhesive layer. Owing to the uniform size of nanoparticles, a nanometric gap junction is formed between the fluid bilayer and PDMS (nanogap-junction). The thickness of the nanogap-junction is controlled by the size of the silica nanoparticles. Target molecules that specifically bind to the receptor molecules in the fluid bilayer are selectively transported into the nanogap-junction via lateral diffusion through the lipid membrane. A thinner gap formed with smaller nanoparticles can enhance the sensitivity (signal-to-background ratio) more effectively, owing to the suppression of nonspecific penetration of coexisting molecules. Silica nanoparticles also provide excellent mechanical robustness, realizing long-term stability of the gap structure. Nanogap-junction using silica nanoparticles provides a versatile platform for highly selective and sensitive sensing by realizing detection of specific target molecules in a solution containing more concentrated nontarget molecules., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Along with their extensively application, human exposure to amorphous silica nanoparticles (SiNPs) has highly increased. Accumulative toxicological researches have provided the scientific correlation between SiNPs exposure and cardiovascular diseases. Endothelial apoptosis is vital in the initiation and progression of atherosclerosis. However, molecular details between SiNPs and endothelial apoptosis remain unidentified. Here, we investigated the uptake and toxic mechanism of SiNPs using HUVECs (Human umbilical vein endothelial cells). Consequently, at 24-h exposure, SiNPs were located freely or within membrane-bound agglomerates in the cytosol, especially in mitochondrial and endoplasmic reticulum (ER) regions with swelled mitochondria, cristae rupture or aggregated ER. Further, we demonstrated that SiNPs induced endothelial apoptosis as evidenced by the Annexin V/PI staining and flow cytometry determination. In line with the ultrastructure alterations, SiNPs triggered mitochondrial ROS generation, ΔΨm collapse, cytosolic Ca 2+ overload, as well as ER stress confirmed by enhanced ER staining, up-regulated GRP78/BiP and XBP1 splicing. More notably, in line with the induction of apoptosis, SiNPs-induced ER stress-associated activation of CHOP, caspase-12, and IRE1α/JNK pathways, which may regulate the BCL2 family member as evidenced by a increased proapoptotic BAX while a decline of anti-apoptotic Bcl-2, ultimately facilitate the mitochondria-mediated apoptotic caspase cascade as confirmed by the upregulated expressions of cytochrome c, Caspase-9 and -3. Altogether, our results indicated the activation of ER stress-mitochondria cascade-mediated apoptotic pathways may be a key mechanism among the SiNPs-induced endothelial apoptosis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

High-performance hemostasis becomes increasingly essential in civilian and military trauma. However, available topical hemostats still exist various drawbacks and side-effects. Herein, a silica nanoparticle coated with polydopamine (PDA/SiNP) with good degradability, antibacterial performance was developed for hemorrhage control. PDA/SiNP formed a porous network via lyophilization and rendered material with phenol hydroxyls, aminos, proper hydrophobicity, promising for further cells aggregation and inducing clotting. The degradation behaviors in vitro indicated that the weight loss of PDA/SiNP could attain approximately 40% just after 24 h. All results demonstrated that clotting time of blood was shortened by nearly 150 s for PDA/SiNP compared with that of commercial Celox in vitro hemostasis. PDA/SiNP could significantly accelerate coagulation by activating the extrinsic pathway of the coagulation cascade, adhering platelets and aggregating erythrocytes. Therefore, not only the PDA/SiNP achieved adequate hemostasis with low exothermic effects, but also blood loss was remarkably reduced in the femoral artery and vein injury, liver injury models. Importantly, PDA/SiNP exhibited long-lasting inhibition of Escherichia coli even after 208 h. Also, the hemolysis of PDA/SiNP with low cytotoxicity was much lower, while erythrocytes maintained regular morphology. Thus, amorphous nanoscale PDA/SiNP provided a new avenue for design of silica hemostats and nonmetallic ion antimicrobial., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As silica nanoparticles (SiNPs) pervade the global economy, however, the followed emissions during the manufacturing, use, and disposal stages inevitably bring an environmental release, potentially result in harmful impacts. Endothelial dysfunction precedes cardiovascular disease, and is often accompanied by mitochondrial impairment and dysfunction. We had reported endothelial dysfunction induced by SiNPs, however, the related mechanisms by which SiNPs interact with mitochondria are not well understood. In the present study, we examined SiNPs-induced mitochondrial dysfunction, and further demonstrated their adverse effects on mitochondrial dynamics and biogenesis in endothelial cells (HUVECs). Consequently, SiNPs entered mitochondria, caused mitochondrial swelling, cristae disruption and even disappearance. Further analyses revealed SiNPs increased the intracellular level of mitochondrial reactive oxygen species, eventually resulting in the collapse of mitochondrial membrane potential, impairments in ATP synthesis, cellular respiration and the activities of three ATP-dependent enzymes (including Na + /K + -ATPase, Ca 2+ -ATPase and Ca 2+ /Mg 2+ -ATPase), as well as an elevated intracellular calcium level. Furthermore, mitochondria in SiNPs-treated HUVECs displayed a fission phenotype. Accordingly, dysregulation of the key gene expressions (FIS1, DRP1, OPA1, Mfn1 and Mfn2) involved in fission/fusion event further certified the SiNPs-induced perturbation of mitochondrial dynamics. Meanwhile, SiNPs-treated HUVECs displayed declined levels of mitochondrial DNA copy number, PGC-1α, NRF1 and also TFAM, indicating an inhibition of mitochondrial biogenesis triggered by SiNPs via PGC-1α-NRF1-TFAM signaling. Overall, SiNPs triggered endothelial toxicity through mitochondria as target, including the induction of mitochondrial dysfunction, as well as the perturbations of their dynamics and biogenesis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: To assess functional effects of silica nanoparticles (SiO 2 -NPs) on human mesenchymal stem cell (hMSC) cardiac integration potential., Methods: SiO 2 -NPs were synthesized and their internalization effects on hMSCs analyzed with particular emphasis on interaction of hMSCs with the cardiac environment Results: SiO 2 -NP internalization affected the area and maturation level of hMSC focal adhesions, accounting for increased in vitro adhesion capacity and augmented engraftment in the myocardial tissue upon cell injection in infarcted isolated rat hearts. SiO 2 -NP treatment also enhanced hMSC expression of Connexin-43, favoring hMSC interaction with cocultured cardiac myoblasts in an ischemia-like environment., Conclusion: These findings provide strong evidence that SiO 2 -NPs actively engage in mediating biological effects, ultimately resulting in augmented hMSC acute cardiac integration potential.

We investigated the effects of targeted functionalized silica nanoparticles on the radiosensitivity of cancer cells. Better control of the local concentration of silica nanoparticles may facilitate their use as an adjuvant in conjunction with ionizing radiation to target cancer cells while preventing damage to normal cells. Hyperbranched polyamidoamine (PAMAM) was grafted onto the surface of amorphous silica nanoparticles to functionalize them. The PAMAM-coated silica nanoparticles (PCSNs) were then conjugated with fluorescent dyes. Anti-HER2 antibodies were covalently attached to the labeled PCSNs. The HER2-overexpressing SK-BR3 breast cancer cell line was incubated in medium containing the PCSN probes. After incubation; the cells were exposed to X-ray radiation. Cells were counted in all samples using cell proliferation assays; and apoptotic cells were detected. The cell survival results showed that the combination of the targeted PCSN probes and radiation reduced the survival rate of SK-BR3 cells to a greater extent than when either PCSN probes, PCSNs or radiation were applied individually. The results also showed an increase in apoptosis in the SK-BR3 cells that internalized the PCSN probes and were then irradiated. Based on these data, PCSN probes act as specific radiosensitizing agents for HER2-overexpressing cells., Competing Interests: The authors declare no conflict of interest.

Follistatin (FST) plays a protective role during silica nanoparticle (SiO 2 NP) exposure. SiO 2 NP treatment induces FST transcription with an unknown mechanism. We herein reported that SIRT6, one of the sirtuin family members, induced epigenetic silencing of FST. The expression of FST was elevated after SIRT6 knockdown while reduced after SIRT6 overexpression. Chromatin immunoprecipitation revealed a direct interaction between SIRT6 with FST promoter. Knockdown of SIRT6 increased both Ac-H3K9 level and Ac-H3K56 level at FST promoter region. SiO 2 NP treatment de-stabilized SIRT6 mRNA and reduced SIRT6 expression, leading to the activation of FST transcription. Finally, over-expression of SIRT6 increased SiO 2 NP-induced apoptosis. Collectively, this study provided evidence that SIRT6 is a negative regulator of FST transcription and participates in the regulation of cell survival during silica nanoparticle exposure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Cationic poly-diallyldimethylammonium (PDADMAC), green CdTe quantum dots (QDs) or red CdS coated CdTe QDs, and anionic polyacrylic acid (PAA) were respectively assembled on the nano-carrier SiO 2 to prepare green fluorescence composite nanoparticles (GF-QDs) and red ones (RF-QDs) with the structure SiO 2 /PDADMAC/QD/PDADMAC/PAA. The sandwich structure "PDADMAC/QD/PDADMAC" on the nano-carrier not only realized the protection to fluorescence of QDs but also avoided the fluorescence shielding of silica shell for the assembled QDs. In 7 days, the diluent solutions of GF-QD and RF-QD all have a very stable fluorescence. On the contrary, the fluorescence of diluent solutions of red and green QDs reduced by 75.99 and 94.35%, respectively. Indeed, they have not fluorescent shielding and have a very slight fluorescent enhancement. Based on GF-QD and RF-QD, the simultaneous determination of Hepatitis B e antigen and surface antigen has been established. Their determination in buffer and plasma all showed good precision and accuracy.

Medical imaging technology using nanoparticles has several advantages from it varies functional properties. As we described previous chapters, mesoporous silica nanoparticles demonstrated great contribution for nanomedicine progress and it has been expected to cause an innovation in medical field. Recently we developed a novel type of silica nanoparticles, organosilica nanoparticles. Organosilica nanoparticles are both structurally and functionally different from common silica nanoparticles by including mesoporous silica nanoparticles. The organosilica nanoparticles are inherent organic-inorganic hybrid nanomaterials. The interior and exterior functionalities of organosilica nanoparticles are effective for their internal and surface functionalization. Medical imaging using organosilica nanoparticles is making a new field of nano-medical imaging. Multifunctionalizations peculiar to organosilica nanoparticles enable to construct novel medical imaging system. In this chapter we will introduce organosilica nanoparticles, and its applications on advanced medical imaging., (© 2018 Elsevier Inc. All rights reserved.)

The effects of the presence of synthesized silica (SS) and exfoliated graphene oxide (EGO) on the removal of sulfide ion with activated sludge (AS) are experimentally investigated. The maximum removal efficiency of sulfide ion for AS without nanoparticles, and the samples with SS and EGO nanoparticles were 81%, 88% and 79%, respectively. Moreover, the maximum elimination capacity (EC max ) for the bioreactor with SS-nanoparticles is 7542 mg/L s, while the EC max of AS and EGO samples were 7075 and 6625 mg/L s, respectively. Two filamentous microbial strains as Gram-negative and Gram-positive bacteria are discerned that removed sulfide ion in the presence of nanoparticles. The measurement of mixture liquor volatile suspended solid that indicates the biomass growth rate during the test shows that the bioreactor containing SS-nanoparticles has more biomass content than the other samples. Our findings indicate that SS-nanoparticles with 0.1% wt. concentration in the bioreactor have no negative effects on the efficiency of the biological removal of sulfide and the presence of SS-nanoparticles even enhances the performance of the bioreactor. On the other side, a bioreactor with EGO nanosheets, as highly antibacterial nanoparticles, with 0.02% wt. concentration significantly influences the microbial growth and reduces sulfide removal efficiency.

Fluorescent light-up probes based on aggregation-induced emission (AIE)-active molecules have recently attracted great research interest due to the intelligent fluorescence activation mechanism and high sensitivity. In this work, an AIE-silica nanosphere (SiO 2 NP)-based label-free fluorescent aptasensor for the sensitive "turn-on" detection of prostate-specific antigen (PSA) is reported for the first time. The positively charged amino-functionalized SiO 2 NPs were used as efficient nanocapturer to electrostatically adsorb single-stranded PSA aptamer (PA) to form SiO 2 NP-PA nanocomposite as well as adsorb negatively charged tetraphenylethylene derivative 3 (TPE3) to form AIE-SiO 2 NP nanocomposite. The binding of the aptamer to the target PSA could induce a rigid aptamer conformation, resulting in the release of the PA away from the surface of SiO 2 NPs. This made the AIE molecules TPE3 aggregate on the SiO 2 NP surface and emit high fluorescence. With the advantages of simple design and rapid responses, the proposed aptasensor showed high sensitivity and selectivity for PSA with a detection limit of 0.5 ng/mL. The aptasensor was further applied in human serum samples with satisfactory results. Given its versatility, high selectivity, and sensitivity, the proposed method could be extended to other targets by varying the recognition probes. Graphical abstract An AIE-SiO 2 NP-based label-free fluorescent aptasensor for the sensitive "turn-on" detection of PSA is reported for the first time.

Little comparative information is available on the detailed intracellular dynamics (diffusion, active movement, and distribution mechanisms) of nanoparticles (≤100nm) and sub-micron particles (>100nm). Here, we quantitatively examined the intracellular movements of different-sized particles and of the endosomal vesicles containing those particles. We showed that silica nanoparticles of various sizes (30 to 100nm) had greater motility than sub-micron particles in A549 cells. Although particles of different sizes localized in the early endosomes, late endosomes, and lysosomes in different proportions, their motilities did not vary, regardless of the vesicles in which they were localized. However, surprisingly, endosomal vesicles containing silica nanoparticles moved faster than those containing sub-micron particles. These results suggest that nanoparticles included within endosomal vesicles do not suppress the motility of the vesicles, whereas sub-micron particles perturb endosomal vesicle transport. Our data support a new hypothesis that differences in particle size influence membrane trafficking of endosomal vesicles., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glutathione (GSH) serves several vital biological functions and its abnormal levels are associated with many diseases. Simple and sensitive methods capable of detecting GSH are desired for better understanding the mechanism of diseases. In this work, a label-free MnO 2 nanosheets assisted aggregation-induced emission (AIE)-silica nanospheres (SiO 2 NPs) nanoprobe for fluorescent "turn-on" detection of GSH with high sensitivity was reported for the first time. The anionic tetraphenylethylene derivative 3 (TPE3) was synthesized and employed as the AIE-active probe, which can be aggregated on the uncoated amino-functionalized SiO 2 NPs to form AIE-SiO 2 NPs and emitted strong fluorescence. Negatively charged MnO 2 nanosheets were employed as both positive charge protectors for amino-functionalized SiO 2 NPs and recognition units for GSH. The presence of GSH could selectively reduce MnO 2 nanosheets to Mn 2+ , thus releasing the amino-functionalized SiO 2 NPs and exposure its positive charges. Accordingly, the TPE3 could be aggregated on the exposured amino-functionalized SiO 2 NPs to form AIE-SiO 2 NPs and emitted strong fluorescence. The proposed assay is simple, fast, low cost, and highly sensitive with a detection limit of 200nM for GSH. The assay was further applied in human serum samples for the detection of GSH with satisfactory results, demonstrating its promising application in practical biological samples., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The encapsulation of fluorescent dyes inside silica nanoparticles is advantageous to improve their quality as probes. Inside the particle, the fluorophore is protected from the external conditions and its main emission parameters remains unchanged even in the presence of quenchers. On the other hand, the amine-functionalized nanoparticle surface enables a wide range of applications, as amino groups could be easily linked with different biomolecules for targeting purposes. This kind of nanoparticle is regularly synthesized by methods that employ templates, additional nanoparticle formation or multiple pathway process. However, a one-step synthesis will be an efficient approach in this sort of bifunctional hybrid nanoparticles. A co-condensation sol-gel synthesis of hybrid fluorescent silica nanoparticle where developed. The chemical and morphological characterization of the particles where investigated by DRIFTS, XPS, SEM and SAXS. The nanoparticle fluorescent properties were also assessed by excitation-emission matrices and time resolved experiments. We have developed a one-pot synthesis method that enables the simultaneous incorporation of functionalities, the fluorescent molecule and the amino group, by controlling co-condensation process. An exhaustive characterization allows the definition of the spatial distribution of the fluorescent probe, fluorescein isothiocyanate, inside the particle and reactive amino groups on the surface of the nanoparticle with diameter about 100nm., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Silica nanoparticles (SiNPs) are being studied and used for medical purposes. As nanotechnology grows rapidly, its biosafety and toxicity have frequently raised concerns. However, diverse results have been reported about the safety of SiNPs; several studies reported that smaller particles might exhibit toxic effects to some cell lines, and larger particles of 100 nm were reported to be genotoxic to the cocultured cells. Here, we investigated the in vivo toxicity of SiNPs of 150 nm in various dosages via intravenous administration in mice. The mice were observed for 14 days before blood examination and histopathological assay. All the mice survived and behaved normally after the administration of nanoparticles. No significant weight change was noted. Blood examinations showed no definite systemic dysfunction of organ systems. Histopathological studies of vital organs confirmed no SiNP-related adverse effects. We concluded that 150 nm SiNPs were biocompatible and safe for in vivo use in mice., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The aim of this paper was to prepare composites of bacterial cellulose (BC) filled with silica (SiO 2 ) nanoparticles to evaluate the influence of the SiO 2 contents (3, 5 and 7wt%) on the thermo-mechanical properties of the composites. BC hydro-gel was immersed in an aqueous solution of silanol derived from tetraethoxysilane (TEOS), the silanol was then converted into SiO 2 in the BC matrix by pressing at 120°C and 2MPa. The BC/SiO 2 translucent sheets were examined by dynamic-mechanical analysis (DMA), thermo gravimetric analysis (TGA), and scanning electron microscopy (SEM). The temperature dependence of the storage modulus, loss modulus and tan delta was determined by DMA. In general, the results revealed that the increment of storage modulus and thermal stability increased concomitantly with the augmentation of SiO 2 content. Therefore, it could be concluded that the mechanical properties of the composites were improved by using high amounts of nano silica. This would be a high aspect ratio of BC capable of connecting the BC matrix and SiO 2 , thereby enhancing a large contact surface and resulting in excellent coherence. A decrease of the storage modulus was consistent with increasing temperature, resulting from softening of the composites. The storage modulus of the composites increased in the order: BC/S7>BC/S5>BC/S3, while the loss modulus and tan delta decreased. On the other hand, the thermal stabilities of all BC/SiO 2 composites were remarkably enhanced as compared to the pristine BC. TGA curves showed that the temperature of decomposition of the pure BC gradually shifted from about 260°C to about 370°C as silica content increased. SEM observations illustrated that the nano-scale SiO 2 was embedded between the voids and nano-fibrils of the BC matrix. Overall, the results indicated that the successful synthesis and superior properties of BC/SiO 2 advocate its effectiveness for various applications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Due to high biocompatibility, polyurethane has found many applications, particularly in development of biomedical devices. A new nanocomposite based on thermoset polyurethane and silica nanoparticles was synthesized using sol-gel method. Sol-gel process was fulfilled in two acidic and basic conditions by using tetraethylorthosilicate (TEOS) and trimethoxyisocyanatesilane as precursors. The hybrid films characterized for mechanical and surface properties using tensile strength, contact angle, ATR-FTIR and scanning electron microscopy. Biocompatibility and cytotoxicity of the hybrids were assessed using standard MTT, LDH and TUNEL assays. The results revealed that incorporation of silica nanoparticles was significantly improved tensile strength and mechanical properties of the hybrids. Based on the contact angle results, silica nanoparticles increased hydrophilicity of the hybrids. Biocompatibility by using human lung epithelial cell line (MRC-5) demonstrated that the hybrids were significantly less cytotoxic compared to pristine polymer as tested by MTT and LDH assays. TUNEL assay revealed no signs of apoptosis in all tested samples. The results of this study demonstrated that incorporation of silica nanoparticles into polyurethane lead to the enhancement of biocompatibility, indicating that these hybrids could potentially be used in biomedical field in particular as a new coating for medical implants., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Both ultrafine particles (UFP) and polycyclic aromatic hydrocarbons (PAHs) are widely present in the environment, thus increasing their chances of exposure to human in the daily life. However, the study on the combined toxicity of UFP and PAHs on respiratory system is still limited. In this study, we examined the potential interactive effects of silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) in bronchial epithelial cells (BEAS-2B). Cells were exposed to SiNPs and B[a]P alone or in combination for 24 h. Co-exposure to SiNPs and B[a]P enhanced the malondialdehyde (MDA) contents and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities significantly, while the reactive oxygen species (ROS) generation had a slight increase in the exposed groups compared to the control but not statistically significant. Cell cycle arrest induced by the co-exposure showed a significant percentage increase in G2/M phase cells and a decrease in G0/G1 phase cells. In addition, there was a significant increase in BEAS-2B cells multinucleation as well as DNA damage. Cellular apoptosis was markedly increased even at the low-level co-exposure. Our results suggest that co-exposure to SiNPs and B[a]P exerts synergistic and additive cytotoxic and genotoxic effects.

Unlabelled: Natural amino acids are zwitterionic molecules and the good biocompatibility promises them potential candidates as anti-fouling materials. Here, we developed a new method to functionalize silica nanoparticles with a natural amino acid-based anti-fouling layer. Amino acids were covalently immobilized on 3-aminopropyltriethoxysilane modified silica nanoparticles using divinyl sulfone through a two-step reaction in aqueous solution at room temperature. The progress was monitored with NMR, X-ray photoelectron spectroscopy (XPS), transmission electron microscope (TEM) and zeta potential measurements. A library of amino acids was screened and the nonspecific protein adsorption of bovine serum albumin (BSA) and fetal bovine serum (FBS) were investigated using dynamic light scattering method. The results showed that cysteine, lysine and arginine functionalized silica nanoparticles can effectively resist protein adsorption due to the zwitterionic structure. Among them, lysine functionalized silica nanoparticles had the best anti-fouling performance, which showed hydrodynamic diameter increases of only 10% after incubated in BSA solution and 20% after incubated in FBS solution for 24h. The neat aqueous modification process can conveniently create a thin zwitterionic layer on silica particles, and it has a great potential in biomolecule immobilization and biofunctional surface preparation., Statement of Significance: Zwitterionic polymer is an outstanding class of anti-fouling material; but the difficulty in synthesis is challenging its spread utilization. In this study, we developed a new method to create an amino acid-based zwitterionic layer on APTES functionalized silica nanoparticles through a two-step reaction in aqueous solution at room temperature. The surface chemistry was monitored with NMR, XPS, TEM and zeta potential measurements. With this method, a library of amino acid conjugated-silica nanoparticles was synthesized and their anti-fouling performance was evaluated using dynamic light scattering method. The results showed that the cysteine, lysine and arginine conjugated nanoparticles all can effectively resist nonspecific protein adsorption. Among them, lysine conjugated nanoparticles show the best anti-fouling performance, which showed hydrodynamic diameter increases of only 10% after incubated in BSA solution and 20% after incubated in FBS solution for 24 hours. These results indicates that the anti-fouling silica nanoparticles are of great potential in many biomedical applications, especially biosensing and diagnose imaging. The modification reactions in aqueous solution at room temperature are easily conducted in laboratory, indicating high potential in the functionalization of silica particles/surfaces with other biomolecules., (Copyright © 2016. Published by Elsevier Ltd.)