The biotransformation of nanoparticles plays a crucial role in determining their biological fate and responses. Although a few engineering strategies (e.g., surface functionalization and shape control) have been employed to regulate the fate of nanoparticles, the genetic control of nanoparticle biotransformation remains an unexplored avenue. Herein, we utilized a CRISPR-based genome-scale knockout approach to identify genes involved in the biotransformation of rare earth oxide (REO) nanoparticles. We found that the biotransformation of REOs in lysosomes could be genetically controlled via SMPD1. Specifically, suppression of SMPD1 inhibited the transformation of La2O3 into sea urchin-shaped structures, thereby protecting against lysosomal damage, proinflammatory cytokine release, pyroptosis and RE-induced pneumoconiosis. Overall, our study provides insight into how to control the biological fate of nanomaterials.
- MeSH
- biotransformace genetika MeSH
- CRISPR-Cas systémy MeSH
- ježovky metabolismus MeSH
- kovové nanočástice * chemie MeSH
- kovy vzácných zemin * metabolismus chemie MeSH
- lidé MeSH
- lyzozomy metabolismus MeSH
- myši MeSH
- nanočástice * metabolismus chemie MeSH
- pyroptóza MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kovy vzácných zemin * MeSH
Imbalanced redox homeostasis, involving either oxidative stress or reductive stress, can profoundly impact cellular functions, contributing to various diseases. While the implications of oxidative stress in the adverse effects of nanoparticles have been extensively studied, our comprehension of reductive stress within the context of nano-redox system interactions remains limited. Here we illuminate a domino effect initiated by the dehydrogenase-like activity of transition metal borides. Specifically, seven transition metal borides were identified to emulate the enzymatic activity of natural dehydrogenases, resulting in heightened levels of reductive constituents within critical biological redox pairs in cells. Mass cytometry analysis provides compelling evidence that reductive stress initiates an immunosuppressive environment within lung tissues, promoting the metastasis of breast cancer cells to the lungs. In summary, our study unveils the chemical basis of nano-induced reductive stress and establishes a mechanistic axis that interlinks dehydrogenase-like activity, reductive stress, immunosuppression and tumour metastasis.
- MeSH
- katalýza MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory plic sekundární imunologie MeSH
- nádory prsu patologie imunologie MeSH
- oxidace-redukce MeSH
- oxidační stres * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Concerns regarding chronic injuries (e.g., fibrosis and carcinogenesis) induced by nanoparticles raised public health concerns and need to be rapidly assessed in hazard identification. Although in silico analysis is commonly used for risk assessment of chemicals, predicting chronic in vivo nanotoxicity remains challenging due to the intricate interactions at multiple interfaces like nano-biofluids and nano-subcellular organelles. Herein, we develop a multimodal feature fusion analysis framework to predict the fibrogenic potential of metal oxide nanoparticles (MeONPs) in female mice. Treating each nano-bio interface as an independent entity, eighty-seven features derived from MeONP-lung interactions are used to develop a machine learning-based predictive framework for lung fibrosis. We identify cell damage and cytokine (IL-1β and TGF-β1) production in macrophages and epithelial cells as key events closely associated with particle size, surface charge, and lysosome interactions. Experimental validations show that the developed in silico model has 85% accuracy. Our findings demonstrate the potential usefulness of this predictive model for risk assessment of nanomaterials and in assisting regulatory decision-making. While the model is developed based on 52 MeONPs, further validation using a larger nanoparticle library is necessary to confirm its broader applicability.
- MeSH
- epitelové buňky účinky léků metabolismus patologie MeSH
- hodnocení rizik metody MeSH
- interleukin-1beta metabolismus MeSH
- kovové nanočástice * toxicita chemie MeSH
- lidé MeSH
- lyzozomy metabolismus účinky léků MeSH
- makrofágy účinky léků metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- plíce patologie účinky léků metabolismus MeSH
- plicní fibróza chemicky indukované patologie metabolismus MeSH
- počítačová simulace MeSH
- strojové učení * MeSH
- transformující růstový faktor beta1 metabolismus MeSH
- velikost částic MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- interleukin-1beta MeSH
- transformující růstový faktor beta1 MeSH
BACKGROUND: The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. METHODS: We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. RESULTS: The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model's prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. CONCLUSIONS: The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.
- Klíčová slova
- biotransformation, lung fibrosis, nanosafety, nanotoxicity, predictive toxicology,
- MeSH
- buňky A549 MeSH
- kovové nanočástice * toxicita chemie MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- plíce účinky léků patologie metabolismus MeSH
- plicní fibróza * chemicky indukované metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The rapid spread of antimicrobial resistance poses a critical threat to global health and the environment. Antimicrobial nanomaterials, including silver nanoparticles (AgNPs), are being explored as innovative solutions; however, the emergence of nanoresistance challenges their effectiveness. Understanding resistance mechanisms is essential for developing antievolutionary strategies. AgNPs exhibit diverse resistance mechanisms, and our findings reveal a dynamic transition between these mechanisms: from flagellin-mediated AgNP precipitation (state I) to activation of the copper efflux pump (CusCFBA) system (state II). We designed targeted physicochemical interventions to counteract these mechanisms. Energy supply blocking was effective for state I, while for state II, neutralizing intracellular acidic pH significantly reduced resistance. These strategies reduced nanoresistance/tolerance by up to 10,000-fold. Additionally, resistance evolution can be completely halted by disrupting the energy supply using carbonyl cyanide 3-chlorophenylhydrazone and overactivating sigma E, one of the key envelope stress regulators that govern resistance transitions. Our findings provide practical strategies to overcome nanoresistance, offering a groundbreaking approach to enhance nanoantimicrobials' efficacy in medical therapies and combat resistance evolution.
- Klíčová slova
- envelope stress, evolutionary transition, nanoresistance, resensitization, silver nanoparticle,
- MeSH
- antibakteriální látky * farmakologie chemie MeSH
- Bacteria účinky léků metabolismus MeSH
- bakteriální léková rezistence účinky léků MeSH
- Escherichia coli účinky léků metabolismus MeSH
- kovové nanočástice * chemie MeSH
- mikrobiální testy citlivosti * MeSH
- stříbro * chemie farmakologie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibakteriální látky * MeSH
- stříbro * MeSH
The outbreak of antibiotic-resistant bacteria, or "superbugs", poses a global public health hazard due to their resilience against the most effective last-line antibiotics. Identifying potent antibacterial agents capable of evading bacterial resistance mechanisms represents the ultimate defense strategy. This study shows that -the otherwise essential micronutrient- manganese turns into a broad-spectrum potent antibiotic when coordinated with a carboxylated nitrogen-doped graphene. This antibiotic material (termed NGA-Mn) not only inhibits the growth of a wide spectrum of multidrug-resistant bacteria but also heals wounds infected by bacteria in vivo and, most importantly, effectively evades bacterial resistance development. NGA-Mn exhibits up to 25-fold higher cytocompatibility to human cells than its minimum bacterial inhibitory concentration, demonstrating its potential as a next-generation antibacterial agent. Experimental findings suggest that NGA-Mn acts on the outer side of the bacterial cell membrane via a multimolecular collective binding, blocking vital functions in both Gram-positive and Gram-negative bacteria. The results underscore the potential of single-atom engineering toward potent antibiotics, offering simultaneously a long-sought solution for evading drug resistance development while being cytocompatible to human cells.
- Klíčová slova
- antibiotic, cytocompatibility, manganese, multi‐drug resistance, single‐atom,
- MeSH
- antibakteriální látky * farmakologie chemie MeSH
- bakteriální léková rezistence * účinky léků MeSH
- dusík chemie MeSH
- grafit chemie farmakologie MeSH
- lidé MeSH
- mangan chemie MeSH
- mikrobiální testy citlivosti * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibakteriální látky * MeSH
- dusík MeSH
- grafit MeSH
- mangan MeSH
Recent research has highlighted the pivotal role of lipoxygenases in modulating ferroptosis and immune responses by catalyzing the generation of lipid peroxides. However, the limitations associated with protein enzymes, such as poor stability, low bioavailability, and high production costs, have motivated researchers to explore biomimetic materials with lipoxygenase-like activity. Here, we report the discovery of lipoxygenase-like two-dimensional (2D) MoS2nanosheets capable of catalyzing lipid peroxidation and inducing ferroptosis. The resulting catalytic products were successfully identified using mass spectrometry and a luminescent substrate. Unlike native lipoxygenases, MoS2 nanosheets exhibited exceptional catalytic activity at extreme pH, high temperature, high ionic strength, and organic solvent conditions. Structure-activity relationship analysis indicates that sulfur atomic vacancy sites on MoS2 nanosheets are responsible for their catalytic activity. Furthermore, the lipoxygenase-like activity of MoS2 nanosheets was demonstrated within mammalian cells and animal tissues, inducing distinctive ferroptotic cell death. In summary, this research introduces an alternative to lipoxygenase to regulate lipid peroxidation in cells, offering a promising avenue for ferroptosis induction.
- Klíčová slova
- ferroptosis, lipid peroxidation, nano-bio interaction, nanobiology, nanocatalyst,
- MeSH
- biomimetické materiály chemie farmakologie metabolismus MeSH
- disulfidy * chemie metabolismus MeSH
- ferroptóza * účinky léků MeSH
- katalýza MeSH
- lidé MeSH
- lipoxygenasa * metabolismus chemie MeSH
- molybden chemie metabolismus MeSH
- myši MeSH
- nanostruktury chemie MeSH
- peroxidace lipidů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- disulfidy * MeSH
- lipoxygenasa * MeSH
- molybden MeSH
- molybdenum disulfide MeSH Prohlížeč
Antimicrobial resistance (AMR) is one of the biggest threats to the environment and health. AMR rapidly invalidates conventional antibiotics, and antimicrobial nanomaterials have been increasingly explored as alternatives. Interestingly, several antimicrobial nanomaterials show AMR-independent antimicrobial effects without detectable new resistance and have therefore been suggested to prevent AMR evolution. In contrast, some are found to trigger the evolution of AMR. Given these seemingly conflicting findings, a timely discussion of the two faces of antimicrobial nanomaterials is urgently needed. This review systematically compares the killing mechanisms and structure-activity relationships of antibiotics and antimicrobial nanomaterials. We then focus on nano-microbe interactions to elucidate the impacts of molecular initiating events on AMR evolution. Finally, we provide an outlook on future antimicrobial nanomaterials and propose design principles for the prevention of AMR evolution.
- Klíčová slova
- Antibacterial Nanomaterials, Antimicrobial Resistance, Killing Mechanism, Nano-Bio Interaction, Structure-Activity Relationship,
- MeSH
- antibakteriální látky * farmakologie MeSH
- bakteriální léková rezistence MeSH
- nanostruktury * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- antibakteriální látky * MeSH
