A multi-mode Rhein-based nano-platform synergizing ferrotherapy/chemotherapy-induced immunotherapy for enhanced tumor therapy.

Ferroptosis has emerged as a promising strategy for treating triple-negative breast cancer (TNBC) due to bypassing apoptosis and triggering immunogenic cell death (ICD) of tumor cells. However, the antitumor efficacy has been limited by the insufficient intracellular ferrous iron concentration required for ferroptosis and inadequate antitumor immune response. To address these limitations, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which exhibited a synergistic effect of ferroptosis, apoptosis and induced immune response for enhanced antitumor therapy. MP-FA@R-F NPs target folate receptors, which are over-expressed on the tumor cell's surface to promote intracellular uptake. The cargoes, including Rhein and Fe3O4, would be released in intracellular acid, accelerating by NIR laser irradiation. The released Rhein induced apoptosis of tumor cells mediated by the caspase 3 signal pathway, while the released Fe3O4 triggered ferroptosis through the Fenton reaction and endowed the nanoplatform with magnetic resonance imaging (MRI) capabilities. In addition, ferroptosis-dying tumor cells could release damage-associated molecular patterns (DAMPs) to promote T cell activation and infiltration for immune response and induce immunogenic cell death (ICD) for tumor immunotherapy. Together, MP-FA@R-F NPs represent a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy. STATEMENT OF SIGNIFICANCE: The massive strategies of cancer therapy based on ferroptosis have been emerging in recent years, which provided new insights into designing materials for cancer therapy. However, the antitumor efficacy of ferroptosis is still unsatisfactory, mainly due to insufficient intracellular pro-ferroptotic stimuli. In the current study, we designed a multi-mode nano-platform (MP-FA@R-F NPs), which represented a potential synergistic ferro-/chemo-/immuno-therapy strategy with MRI guidance for enhanced antitumor therapy.

Long-term polystyrene nanoplastic exposure disrupt hepatic lipid metabolism and cause atherosclerosis in ApoE-/- mice.

Nanoplastics (NPs) exposure is usually linked with abnormal inflammation and oxidative stress, which are high-risk triggers of atherosclerosis; however, whether this exposure causes the development of atherosclerosis is vague. Here, we found that PS NPs co-exposure with ox-LDL induces significant accumulation of lipid, as well as oxidative stress and inflammation in RAW264.7 macrophages. Using an ultrasound biomicroscope (UBM), we observed the emergence of atherosclerotic plaques at the aortic arch of apolipoprotein knockout (ApoE-/-) mice after being exposed to PS NPs for three months. Oil-red O and hematoxylin-eosin (H&E) staining at the mice's aortic root also observed the deposition of lipids with plaque formation. Moreover, the development of atherosclerotic disease is associated with disturbances in lipid metabolism and oxidative stress damage in the mice liver. In conclusion, this study provides additional evidence to further understand the possible cardiovascular damage caused by NPs exposure.

Exosome Heterogeneity Affects the Distal "Barrier-Crossing" Trafficking of Exosome Encapsulated Quantum Dots.

The biological activities of nanoparticles (NPs), which include endocytosis by macrophages and subsequent intracellular degradation and/or release, transfer to other cells, or translocation across tissue barriers, highly depend on their fate in living organisms. Yet, translocation across barriers, especially the distal "barrier-crossing" trafficking of NPs, is still unclear. The exosome (Exo) plays a crucial role in intercellular communication and biological barrier trafficking. Here, we report that ZnCdSe@ZnS quantum dots (QDs), as a representation of NPs in biomedical applications, could cross the blood-brain barrier and approach the mouse brain via active Exo encapsulation. By employing multiple techniques, we demonstrated that QDs were internalized by macrophages (J774A.1) and tumor cells (HeLa) and then released to the extracellular environment along with Exo. Exo encapsulation facilitates the distal barrier-crossing trafficking of QDs in vivo, while Exo biogenesis inhibitor GW4869 suppressed the QDs enriched in the brains of mice with a 4T1-Luc breast cancer xenograft. Interestingly, Exo heterogeneity affects the distal trafficking of enveloped QDs. Exo derived from tumorous HeLa cells, not macrophages, that were enriched in functional proteins with cell adhesion, cell migration, axon guidance, and cell motility, showed a better capacity for the remote trafficking of QDs. This study proposes Exo as a vehicle to deliver exogenous NPs to translocate across the distal barrier and provides further information for biomedical application and the risk assessment of NPs.

Oral exposure of polystyrene microplastics and doxycycline affects mice neurological function via gut microbiota disruption: The orchestrating role of fecal microbiota transplantation.

The debris of plastics with a size < 5 mm, called microplastics, possess long-lived legacies of plastic pollution and a growing threat to human beings. The adverse effects and corresponding molecular mechanisms of microplastics are still largely unknown and must be prioritized. Antibiotics commonly co-existed with microplastics; the current study investigated the syngenetic toxic effect of doxycycline (Dox) and polystyrene microplastics (PS). Specifically, we found that Dox combined with PS exposure perturbed gut microbiota homeostasis in mice, which mediated brain lesions and inflammation with a concomitant decline in learning and memory behaviors through the gut-brain axis. Of note, PS exposure resulted in intestinal damage and structural change, but Dox did not accelerate the disruption of intestinal barrier integrity in PS-treated mice. Interestingly, fecal microbiota transplantation (FMT) can reverse neurological impairment caused by combined PS and Dox exposure via compensating gut microbes; therefore, the learning and memory abilities of mice were also recovered. This work not only provides insights into the syngenetic effect of microplastics and antibiotics and highlights their distal neurotoxicity through the gut-brain axis but also offers a promising strategy against their combined toxicity.

Coronal ApoE Protein Combines with LRP1 to Inactivate GSK3ß That Mitigates Silica Nanoparticle-Induced Brain Lesion.

Silica nanoparticles (SiO2 NPs) are widely used engineered materials that warrant their obvious environmental exposure risk. Our previous study has shown that different routes of SiO2 NP exposure on the glycogen synthase kinase 3 beta (GSK3ß) activity were related to the serum proteins enriched on the surface of SiO2 NPs, which implied that a particular protein in the serum changed the inherent toxic behavior of SiO2 NPs and inhibited the activation of GSK3ß by SiO2 NPs. Here, we identified that the SiO2 NP surface enriched a large amount of apolipoprotein E (ApoE), and the ApoE protein corona bound to the lipoprotein receptor-related protein 1 (LRP1) to inactivate GSK3ß, thereby reducing the damage of SiO2 NPs to the brain. This work presented the first evidence that specific biocorona reduced the toxicity of SiO2 NPs at the molecular level, which helped to elucidate the role of specific corona components on nanotoxicity.

Silica Nanoparticle Exposure Implicates ß-Amyloid (1-42) Inbound and the Accelerating Alzheimer's Disease Progression in Mice Overexpressing Mutated Forms of Human Amyloid Precursor Protein and Presenilin 1 Genes.

The increasing nanoparticle (NP) applications in the biomedical field have become an emerging concern regarding human health. NP exposure may play a role in the accelerating Alzheimer's disease (AD) progression; however, the etiology of this disorder is complex and remains largely unclear. Here, we identified that intravenous injection of silica NPs (SiNPs) caused the blood-brain barrier breakdown via downregulating tight junction-related gene expressions. Meanwhile, SiNPs upregulate the transport receptor for advanced glycation end products (RAGE) that govern the ß-amyloid (Aß) influx to the brain; however, low-density lipoprotein receptor-related protein 1 (LRP1) that controls the efflux of Aß from the brain was not affected. Consequently, an increase in Aß burden in the brain of SiNP-challenged APP/PS1 mice was found. Intriguingly, plasma apolipoprotein E (ApoE) adsorbed on the surface of SiNPs partially relieves this effect. Using ApoE knockout (ApoE-/-) mice, we confirmed that SiNPs covered with serum without ApoE showed further elevated AD symptoms. Together, this study offered a compilation of data to support the potential risk factors of NP exposure and AD pathology.

Environmentally Relevant Concentrations of Microplastic Exposure Cause Cholestasis and Bile Acid Metabolism Dysregulation through a Gut-Liver Loop in Mice.

The massive production of plastics causes the ubiquitous existence of microplastics (MPs) in the biota, therefore, posing exposure risks and potential health concerns to human beings. However, the exact mechanisms of MPs-induced toxicities and abnormalities are largely unknown. In this study, we developed a mouse model of gavage polystyrene microplastics (PS MPs) for 30 days. We found that PS MPs can damage the intestinal barrier, accumulate in the liver tissue, and cause injury. The liver and intestine are both highly associated with bile acid (BA) metabolism. Indeed, we found that PS MPs dysregulate BA synthesis and efflux-related gene expression in the liver, causing cholestasis. Tandemly, PS MPs alter the ratio of primary to secondary BA in the feces by affecting the composition of the intestinal flora. At last, PS MPs alter mice's fecal BA profile, which affects normal BA metabolism. Taken together, the present study provides robust data on the mechanism of toxicity of MPs causing the disturbance of BA metabolism via a 4-step gut-liver loop.

Long-term pulmonary iron oxide nanoparticles exposure disrupts hepatic iron-lipid homeostasis and increases plaque vulnerability in ApoE-/- mice.

Iron oxide nanoparticles (Fe3O4 NPs) have attracted great attention due to their extensive applications, which warranted their environmental concerns. Although recent advances have proposed the relevance of Fe3O4 NPs to cardiovascular disease, the intrinsic mechanisms underlying the effects of NPs remain indistinct. ApoE-/- mice were chosen as a long-term exposure model to explore the immanent association between respiratory exposure to Fe3O4 NPs and the development of cardiovascular diseases. Pulmonary exposure to 20 nm and 200 nm Fe3O4 NPS resulted in significant lung injury, and pulmonary histopathological examination displayed inflammatory cell infiltration, septal thickening and alveolar congestion. Intriguingly, liver iron deposition and variations in the hepatic lipid homeostasis were found in Fe3O4 NPs-exposed mice, eventually leading to dyslipidemia, hinting the potential cardiovascular toxicity of Fe3O4 NPs. In addition, we not only found that Fe3O4 NPs exposure increased aortic plaque area, but also increased M1 macrophages in the plaque, which yielding plaque vulnerability in ApoE-/- mice Of note, 20 nm Fe3O4 NPs showed enhanced capability on the progression of atherosclerosis than 200 nm Fe3O4 NPs. This study may propose the potential mechanism for adverse cardiovascular disease induced by Fe3O4 NPs and provide convincing evidence for the safety evaluation of Fe3O4 NPs.

Azo Reductase Activated Magnetic Resonance Tuning Probe with "Switch-On" Property for Specific and Sensitive Tumor Imaging in Vivo.

Cancer remains a threat to human health. However, if tumors can be detected in the early stage, then the effectiveness of cancer treatment could be significantly improved. Therefore, it is worthwhile to develop more sensitive and accurate cancer diagnostic methods. Herein, we demonstrated an azo reductase (AzoR)-activated magnetic resonance tuning (MRET) probe with a "switch-on" property for specific and sensitive tumor imaging in vivo. Specifically, Gd-labeled DNA1 (DNA1-Gd) and cyclodextrin-coated magnetic nanoparticles (MNP-CD) were employed as enhancer and quencher of MRET, respectively, while DNA2, an azobenzene (Azo) group-modified aptamer (AS1411), served as a linker between enhancer and quencher to construct the MRET probe of MNP@DNA(1-2)-Gd. In tumor tissues with high-level AzoR, the T1-weighted magnetic resonance signal of the MRET probe could be restored by intelligently regulating the switch from "OFF" to "ON" after activation with AzoR, thus accurately indicating the location of the tumor accurately. Moreover, the tumor with a 4 times smaller size than that of the normal tumor model could be imaged based on the proposed MRET probe. The as-proposed MRET-based magnetic resonance imaging strategy not only achieves tumor imaging accurately but also shows promise for early diagnosis of tumors, which might improve patients' survival rates and provide an opportunity for image-guided biomedical applications in the future.

The redox activity of polychlorinated biphenyl quinone metabolite orchestrates its pro-atherosclerosis effect via CAV1 phosphorylation.

Further investigations are required to prove that polychlorinated biphenyls (PCBs) exposure is a cardiovascular disease risk factor. Unlike previous studies that attributed the atherogenic effect of PCBs to aryl hydrocarbon receptor activation, we illustrated a new mechanism involved in the redox reactivity of PCBs. We discover the redox reactivity of quinone moiety is the primary factor for PCB29-pQ-induced proinflammatory response, which highly depends on the status of caveolin 1 (CAV1) phosphorylation. PCB29-pQ-mediated CAV1 phosphorylation disrupts endothelial nitric oxide synthase, toll-like receptor 4, and reduces interleukin-1 receptor-associated kinase 1 binding with CAV1. Phosphorylated proteomics analysis indicated that PCB29-pQ treatment significantly enriched phosphorylated peptides in protein binding functions, inflammation, and apoptosis signaling. Meanwhile, apolipoprotein E knockout (ApoE-/-) mice exposed to PCB29-pQ had increased atherosclerotic plaques compared to the vehicle group, while this effect was significantly reduced in ApoE-/-/CAV1-/- double knockout mice. Thus, we hypothesis CAV1 is a platform for proinflammatory cascades induced by PCB29-pQ on atherosclerotic processes. Together, these findings confirm that the redox activity of PCB metabolite plays a role in the etiology of atherosclerosis.

Transferrin-Targeted Cascade Nanoplatform for Inhibiting Transcription Factor Nuclear Factor Erythroid 2-Related Factor 2 and Enhancing Ferroptosis Anticancer Therapy.

Ferroptosis, an iron-dependent cell death driven by the lethal levels of lipid peroxidation (LPO), becomes a promising anticancer strategy. However, the anticancer efficacy of ferroptosis is often hindered by the activation of nuclear factor erythrocyte 2-associated factor 2 (Nrf2), which is an indispensable regulator of the cellular antioxidant balance by preventing the accumulation of intracellular reactive oxygen species (ROS). Herein, we present a rational design of a Tf-targeted cascade nanoplatform TPM@AM based on mesoporous polydopamine (MPDA) co-encapsulating a ferroptosis inducer (artesunate, ART) and an Nrf2-specific inhibitor (ML385) to enhance intracellular ROS and therefore amplify ferrotherapy. Transferrin (Tf) can specifically recognize the transferrin receptor (TfR) on the surface of the cell membrane, which binds and transports iron into cells. When TPM@AM is endocytosed, the high-acid tumor microenvironment and laser irradiation trigger the collapse of MPDA to release ART and ML385. Furthermore, MPDA endows the nanoplatform with photothermal capability. The nanoplatform exhibits high efficiency for synergistic tumor suppression, representing a spatiotemporal controllable therapeutic strategy for precise synergistic cancer therapy.

Silicon dioxide nanoparticles adsorption alters the secondary and tertiary structures of catalase and undermines its activity.

The expanding production and use of nanomaterials in various fields caused big concern for human health. Oxidative stress is the most frequently described mechanism of nanomaterial toxicity. A state of oxidative stress can be defined as the imbalance of reactive oxygen species (ROS) production and antioxidant enzyme activities. Although nanomaterials-triggered ROS generation has been extensively investigated, little is known regarding the regulation of antioxidant enzyme activities by nanomaterials. This study used two typical nanomaterials, SiO2 nanoparticles (NPs) and TiO2 NPs, to predict their binding affinities and interactions with antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). The molecular docking results showed that CAT and SOD had different binding sites, binding affinity, and interaction modes with SiO2 NPs and TiO2 NPs. The binding affinities of the two NPs to CAT were more potent than those to SOD. Consistently, the experimental work indicated NPs adsorption caused the perturbation of the second and tertiary structures of both enzymes and thus resulted in the loss of enzyme activities.

Long-term exposure of molybdenum disulfide nanosheets leads to hepatic lipid accumulation and atherogenesis in apolipoprotein E deficient mice.

Before their large-scale applications, it is necessary to understand the biological effects of nanomaterials. Although two-dimensional nanomaterials (2D NMs) molybdenum disulfide nanosheets (MoS2 NSs) are promising in biomedical fields, the current knowledge regarding their toxicities is inadequate. Using apolipoprotein E deficient (ApoE-/-) mice as a long-term exposure model, this study demonstrated that intravenous (i.v.) injection of MoS2 NSs most accumulated in the liver and caused in situ hepatic damage. Histopathological examination indicated severe infiltration of inflammatory cells and irregular central veins in the MoS2 NSs-treated mouse liver. Meanwhile, the overwhelming expressions of inflammatory cytokines, dyslipidemia, and dysregulated hepatic lipid metabolism implied the potential vascular toxicity of MoS2 NSs. Indeed, our result supported that MoS2 NSs exposure is highly associated with atherosclerotic progression. This study provided the first line of evidence on the vascular toxicity of MoS2 NSs, which remind scientists to pay attention to the rational use of MoS2 NSs, especially in the biomedical fields.

A pH-responsive magnetic resonance tuning probe for precise imaging of bacterial infection in vivo.

Accurate and sensitive detection of bacteria is essential for treating bacterial infections. Herein, a pH-responsive magnetic resonance tuning (MRET) probe, whose T1-weighted signal is activated in the bacteria-infected acid microenvironment, is developed for in situ accurately magnetic resonance imaging (MRI) of bacterial infection in vivo. The MRET probe (MDVG-1) is an assembly of paramagnetic enhancer (gadolinium-modified i-motif DNA3, abbreviated as Gd-DNA3-Gd) and the precursor of superparamagnetic quencher (DNA and vancomycin-modified magnetic nanoparticle, abbreviated as MDV). The T1-weighted signal of Gd-DNA3-Gd is quenched once the formation of MDVG-1 (MRET ON). Interestingly, the MDVG-1 probe was disassembled into the monomers of Gd-DNA3-Gd and MDV under the bacteria-infected acid microenvironment, resulting significantly enhanced T1-weighted signal at the infected site (MRET OFF). The pH-responsive MRET probe-based enhanced MRI signal and bacteria targeting significantly improve the distinction between bacterial infectious tissues and sterile inflamed tissues, which provides a promising approach for accurately detecting bacterial infection in vivo. STATEMENT OF SIGNIFICANCE: Detecting pathogenic bacteria in vivo based on magnetic resonance imaging (MRI) strategy has been exploring recently. Although various bacterial-targeted MRI probes have been developed to image bacteria in vivo, the MRI signal of these MRI probes is always "on", which inevitably generates nonspecific background MRI signals, affecting the accuracy of MRI to a certain extent. In the current study, based on the magnetic resonance tuning (MRET) phenomenon, we present a pH-responsive MRET probe (MDVG-1) with T2-weighted imaging to T1-weighted imaging switchable properties to achieve in situ precise imaging of bacterial infection in vivo.

Enzyme-Triggered Transforming of Assembly Peptide-Modified Magnetic Resonance-Tuned Probe for Highly Sensitive Imaging of Bacterial Infection In Vivo.

Confirming bacterial infection at an early stage and distinguishing between sterile inflammation and bacterial infection is still highly needed for efficient treatment. Here, in situ highly sensitive magnetic resonance imaging (MRI) bacterial infection in vivo based on a peptide-modified magnetic resonance tuning (MRET) probe (MPD-1) that responds to matrix metallopeptidase 2 (MMP-2) highly expressed in bacteria-infected microenvironments is achieved. MPD-1 is an assembly of magnetic nanoparticle (MNP) bearing with gadolinium ion (Gd3+ ) modified MMP-2-cleavable self-assembled peptide (P1 ) and bacteria-targeting peptide (P), and it shows T2 -weighted signal due to the assemble of MNP and MRET ON phenomenon between MNP assembly and Gd3+ . Once MPD-1 accumulates at the bacterially infected site, P1 included in MPD-1 is cleaved explicitly by MMP-2, which triggers the T2 contrast agent of MPD-1 to disassemble into the monomer of MNP, leading the recovery of T1 -weighted signal. Simultaneously, Gd3+ detaches from MNP, further enhancing the T1 -weighted signal due to MRET OFF. The sensitive MRI of Staphylococcus aureus (low to 104 CFU) at the myositis site and accurate differentiation between sterile inflammation and bacterial infection based on the proposed MPD-1 probe suggests that this novel probe would be a promising candidate for efficiently detecting bacterial infection in vivo.

Mechanistic Insights of TiO2 Nanoparticles with Different Surface Charges on Aß42 Peptide Early Aggregation: An In Vitro and In Silico Study.

Humans may intendedly or unintendedly be exposed to nanomaterials through food, water, and air. Upon exposure, nanomaterials can pierce the bloodstream and translocate to secondary organs, including the brain, which warrants increased concern for the potential health impacts of nanomaterials. Due to their large surface area and interaction energy, nanomaterials can adsorb surrounding proteins. The misfolding and self-aggregation of amyloid-ß (Aß) have been considered significant factors in the pathogenesis of Alzheimer's disease. We thus hypothesize that brain-targeted nanomaterials may modulate Aß aggregation and cause related neurotoxicity. Here, we showed that TiO2 nanoparticles (NPs) and their aminated analogue (TiO2-NH2 NPs) adsorb the Aß42 peptide and accelerate its early oligomerization. Molecular dynamics simulation indicated that the adsorption onto TiO2 NPs and TiO2-NH2 NPs surfaces can stabilize the ß-sheet-rich conformations formed by the Aß42 peptide. The binding sites between TiO2-NH2 NPs and the Aß42 oligomer surface were mainly concentrated in the hydrophobic core region, and the ß-sheet conformation spontaneously formed by Aß42 oligomers can be better stabilized through a hydrogen bond, electrostatic attraction, and hydrophobic interaction. This study will further help in the understanding of nanomaterial-related neurotoxicities and the regulation of their applications.

Polybrominated diphenyl ether quinone exposure leads to ROS-driven lysosomal damage, mitochondrial dysfunction and NLRP3 inflammasome activation.

Polybrominated diphenyl ethers (PBDEs) are aromatic compounds that containing bromine atoms, which possess high efficiency, good thermal stability. However, PBDEs had various known toxic effects and were characterized as persistent environmental pollutants. Exposure to a quinone-type metabolite of PBDEs (PBDEQ) is linked with excess production of intracellular reactive oxygen species (ROS) in our previous studies. Here, we observed that PBDEQ exposure led to ROS and mitochondrial dysfunction, which promoted canonical and non-canonical Nod-like receptor protein 3 (NLRP3) inflammasome activation. Further experiments demonstrated that PBDEQ exposure activated Toll-like receptors (TLRs), subsequently regulating nuclear factor kappa B (NF-κB) signaling. Moreover, lysosomal damage and K+ efflux were involved in PBDEQ-driven NLRP3 inflammasome activation. Our in vivo study also illustrated that PBDEQ administration induced liver inflammation in male C57BL/6J mice. Cumulatively, our current finding provided novel insights into PBDEQ-induced pro-inflammatory responses.

Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of "sword and shield" theory.

Ferroptosis provide new insights into designing nanomedicines for enhanced cancer therapy; however, its antitumor efficacy is relatively low, mainly due to self-protective mechanism of cancer cells, e.g., heat shock protein (HSP) overexpression. Since HSPs can be modified/inhibited by lipid peroxidation (LPO) ending products, we construct a nanoplatform, namely MPDA@Fe3O4-Era, to amplify intracellular reactive oxygen species (ROS) and LPO for synergistic ferrotherapy. Upon tumor acidic microenvironment and local near-infrared stimuli, this nanoplatform releases Fe3O4 and reacts with intracellular hydrogen peroxide (H2O2) to promote Fenton reaction, and yields significant intracellular ROS (specifically hydroxyl radical, •OH) and LPO. In turn, LPO ending products crosslink HSPs to destroy self-preservation pathways of cancer cells to enhance anticancer effect. Meanwhile, the released erastin inhibits system XC - signal pathway to depletes glutathione. Fe3O4 loading further provides magnetic resonance imaging T2-weighted signal to guide anti-tumor treatment. Together, this nanoplatform not only provides •OH (as a "sword" to attack tumor cells), but also inhibits system XC - signal pathway and crosslinks HSP (break down the "shield" of tumor cells) to maximize synergistic ferro-therapeutic effect. MPDA@Fe3O4-Era plus laser irradiation possessed highly efficient tumor suppression with magnified the levels of •OH and inactive glutathione peroxidase 4 (GPX4), which can promote the development of precise cooperative cancer therapy.

Eryptosis is an indicator of hematotoxicity in the risk assessment of environmental amorphous silica nanoparticles exposure: The role of macromolecule corona.

Silica nanoparticles (SiO2 NPs) have been widely manufactured for various applications and unintentionally generated in various industrial processes. SiO2 NPs exposure is potentially hazardous to human health. Incremental evidence has indicated the presence of SiO2 NPs in systemic circulation, which warranted their interaction with blood components. Due to the obvious weakness of hemolysis in the risk assessment of environmental NPs, we for the first time use eryptosis as a sensitive indicator to assess the hematotoxicity of SiO2 NPs. In vitro results showed that the exposure of erythrocytes to pristine SiO2 NPs resulted in typical features of eryptosis, including oxidative stress, calcium influx, phosphatidylserine externalization and hemolysis. However, SiO2 NPs covered with mouse plasma (SiO2@MP) or grafted with polyvinylpyrrolidone (SiO2@PVP) did not stimulate eryptosis. Interestingly, neither bare nor macromolecule-decolorated SiO2 NPs caused eryptosis in our in vivo mouse model, highlighting the protective role of coronal proteins on the amelioration of SiO2 NPs-induced hematotoxicity. These results emphasized the influences of surface modification on the toxicity of environmental NPs.

CRISPR/Cas13a assisted amplification of magnetic relaxation switching sensing for accurate detection of miRNA-21 in human serum.

Development of rapid and accurate detection of miRNAs in complex samples is of great significance for potential early diagnosis of disease. Herein, we report a magnetic relaxation switching (MRS)-based strategy for direct detection of miRNAs in complex samples via the assistance of signal amplification system of CRISPR/Cas13a which has the ability to specifically recognize target RNA. In the designed strategy, 30 nm-magnetic nanoparticles (MB30) and 1000 nm-magnetic particles (MM1000) linked by single-strand RNA1 complexes (MB30-RNA1- MM1000) were employed as signal probe. After the target miRNAs (taking miR-21 as model) recognition by CRISPR/Cas13a system, the resulted trans-cleavage degrades the MB30-RNA1-MM1000, releasing MB30 which caused transverse relaxation time (T2) signal change. The combination of CRISPR/Cas13a assisted signal amplification and the MRS assay achieved direct detection of miR-21 in the serum sample without extracting within 60min, with a detection limit of 0.22 pM. Moreover, the detection accuracy is confirmed by performing the detection of miR-21 using qRT-PCR. The CRISPR/Cas13a system assisted MRS assay successfully achieved accurate, simple, and rapid detection of miRNAs in complex samples, showing great potential for detection miRNAs in potential clinical applications.