Tina Buerki-Thurnherr

Commercial products incorporating graphene‐based two‐dimensional (2D) nanosheets are increasingly developed to enhance mechanical, thermal, and electrical performance. Potential release of inhalable particles during manufacturing or end‐of‐life processing, however, raises concerns regarding respiratory health. This study explored the pulmonary cytotoxicity and immunomodulatory activity of airborne particles generated by mechanical abrasion of industrially relevant few‐layer graphene (FLG) reinforced epoxy composites. A multimodal analytical strategy combining high‐resolution transmission electron microscopy, Raman microscopy, and time‐of‐flight secondary ion mass spectrometry enabled reliable detection and spatial mapping of FLG in pristine and abraded composites. Abrasion predominantly produced composite fragments in which FLG remained embedded, with no indication of protruding or freely released FLG nanosheets. Across advanced bronchial and alveolar epithelial air–liquid interface models, neither abraded epoxy nor FLG–epoxy particles induced cytotoxic or pro‐inflammatory responses. A moderate reduction of mucociliary clearance was observed only at high exposure doses of abraded epoxy particles, without amplification by FLG reinforcement. As‐produced FLG triggered strong TNF‐α secretion in alveolar macrophages, whereas abraded FLG–epoxy particles elicited minimal responses. Overall, the findings indicate limited acute respiratory toxicity associated with inhalation of fragments released from FLG‐based epoxy composites under production and end‐of‐life scenarios.

Developmental toxicity assessment currently relies predominantly on in vivo animal studies that provide limited mechanistic insights into human-relevant effects of drugs, nanoparticles (NPs), or environmental pollutants during pregnancy. To bridge this gap, we developed an innovative human-based co-culture platform on a microfluidic chip that integrates a placental barrier model with a human induced pluripotent stem cell (hiPSC)-derived embryoid body (EB) to model early embryonic development. The placental model consists of primary cytotrophoblast (CTB) cells from human term placenta and human placental vascular endothelial cells (HPVECs). CTBs formed a spontaneous syncytialized trophoblast layer with preserved endocrine function and predictable transport of drugs and NPs, while EBs maintained germ-layer differentiation capacity during co-culturing. Exposure to the known teratogen valproic acid disrupted neuroectodermal features in EBs only in the presence of the placental barrier, while the placenta prevented the accumulation of all-trans retinoic acid in the embryonic compartment, demonstrating that placental transport, metabolism, and signalling actively modulate developmental toxicity outcomes. Overall, our platform reproduces key features of the dynamic placenta-embryo interplay and provides a human-relevant in vitro system for mechanistic studies of placental contributions to developmental toxicity.

Air pollution, particularly from airborne particulate matter (PM), is a major global health challenge and a leading cause of premature death. In this perspective, we provide an overview of human exposure routes to airborne PM and engineered nanoparticles, their subsequent translocation across biological barriers, and their biological effects within barrier tissues and beyond with a focus on the pulmonary and placental barrier. Emphasis is placed on direct versus indirect toxicity mechanisms in the absence of barrier crossing as well as on the ‘Trojan Horse effect’ that can enhance toxicity. Based on the current state of research, we outline critical knowledge gaps and highlight selected research efforts with Swiss participation that seeks to address these challenges. Collectively, these efforts will contribute to advancing risk assessment frameworks, informing regulatory policy, and ultimately reducing the global health burden of particle exposure.

For the successful commercial development of emerging 2D materials, it is crucial to understand their potential biological effects on healthy and diseased individuals. The present study demonstrates that a repeated low‐dose (1 µg cm ⁻² for 5 weeks) exposure of primary human broncho‐epithelial (HBE) cell cultures to hexagonal boron nitride nanosheets ( h ‐BN) and boron nitride nanotubes (BNNTs) increases the phospholipid, sphingolipid, and diglyceride content in cell membranes. Global lipidomics profiling further shows the induction of lipid mediator biosynthesis, especially after exposure to BNNTs in asthmatic cell cultures. The significant increase in leukotriene biosynthesis including its extracellular release is also confirmed in vivo in exposed mouse lungs. Mechanistically, extracellular release of lipid mediators prompts the recruitment and activation of immune cells. Mass cytometry‐based single‐cell profiling of human peripheral blood mononuclear cells reveals the activation of distinct lymphocyte populations expressing cytotoxic granzyme B and perforin mainly after exposure to conditioned medium from BNNT‐exposed asthmatic HBE cultures. These findings unveil the sub‐cytotoxic impact of BN nanomaterials on cellular lipid homeostasis and associated immunomodulation from repeated‐dose exposures, which may pose a potential health hazard, particularly for immune‐compromised individuals, and therefore, needs to be considered for the responsible and sustainable production and use of BN‐based products.

The success of medical devices and biomaterials hinges on selecting biological models that truly reflect human physiology and disease. A well‐chosen model is not just a scientific necessity; it is a clinical imperative. Academic biomedical research often relies on readily accessible models that yield affordable, convenient, and predictable results. However, rodent models of sepsis, cancer, and cardiovascular disease frequently fail in clinical translation. Likewise, optimizing a device or material to fit a specific model (“overfitting”) can create false confidence, leading to expensive setbacks. While in vitro systems offer ethical advantages and mechanistic insights, they lack the complexity of living organisms. Animal models, though capable of capturing systemic effects, face species differences, ethical concerns, and poor clinical translation. Advances in 3D tissue engineering, organ‐on‐a‐chip, and humanized models overcome many of these shortcomings, improving predictive accuracy and complementing animal models. Clinician involvement is crucial to aligning preclinical models with real‐world medical needs. Moreover, unnecessary animal experiments should not be conducted or required without a clear translational route. Prioritizing clinically relevant models enhances patient safety, reduces research waste, and drives ethical, impactful medical innovation.

The respiratory tract possesses mucociliary-driven innate immune defense mechanisms that protect the lungs from harmful environmental exposures, but when damaged, increase susceptibility to respiratory infections and diseases. Inhalation exposure to certain nanomaterials has been shown to trigger fibrosis and other respiratory conditions. However, there is a limited understanding of whether nanomaterials can impair mucociliary defense in lungs and its underlying mechanism. Here, we first investigated the fate of zero-dimensional, one-dimensional, and two-dimensional silicon- and carbon-based nanomaterials (silicon carbide nanowires (SiC NWs), silicon dioxide (SiO₂), multiwalled carbon nanotubes (MWCNTs), and graphene nanosheets) in airway mucus. The results demonstrated that only SiC NWs escaped through the mucus gel without interactions, suggesting their potential to diffuse across the protective mucus layer. The hydrophobicity of the SiC NWs, associated with the low abundance of polar surface groups, such as silanols, was mainly responsible for the observed shielding of particle interactions with mucus components. Furthermore, repeated exposure to SiC NWs in primary bronchial epithelial cell cultures revealed abnormal ciliary structure and significantly (p < 0.05) compromised mucociliary clearance functions, however, no such effects were evident for other particles. mRNA expression analysis showed a significant (p < 0.05) increase in FOX-J1 transcripts, suggesting transcriptional dysregulation of ciliogenesis after exposure to SiC NWs. Finally, SiC NWs reduced epithelial barrier integrity and promoted pro-inflammatory and pro-fibrotic responses. These findings unravel the hazardous potential of SiC NWs upon inhalation exposure and identify the breaching and impairment of the mucociliary innate defense as a key event in their respiratory toxicity.

Oxidative stress and inflammation are at the root of a multitude of diseases. Treatment of these conditions is often necessary but current standard therapies to fight excessive reactive oxygen species (ROS) and inflammation are often ineffective or complicated by substantial safety concerns. Nanozymes are emerging nanomaterials with intrinsic enzyme‐like properties that hold great promise for effective cancer treatment, bacterial elimination, and anti‐inflammatory/anti‐oxidant therapy. While there is rapid progress in tailoring their catalytic activities as evidenced by the recent integration of single‐atom catalysts (SACs) to create next‐generation nanozymes with superior activity, selectivity, and stability, a better understanding and tuning of their safety profile is imperative for successful clinical translation. This review outlines the current applied safety assessment approaches and provides a comprehensive summary of the safety knowledge of therapeutic nanozymes. Overall, nanozymes so far show good in vitro and in vivo biocompatibility despite considerable differences in their composition and enzymatic activities. However, current safety investigations mostly cover a limited set of basic toxicological endpoints, which do not allow for a thorough and deep assessment. Ultimately, remaining research gaps that should be carefully addressed in future studies are highlighted, to optimize the safety profile of therapeutic nanozymes early in their pre‐clinical development.

Exposure to nanoparticles (NPs) in pregnancy is increasingly linked to adverse effects on embryo‐fetal development and health later in life. However, the developmental toxicity mechanisms of NPs are largely unknown, in particular potential effects on the placental secretome, which orchestrates many developmental processes pivotal for pregnancy success. This study demonstrates extensive material‐ and pregnancy stage‐specific deregulation of placental signaling from a single exposure of human placental explants to physiologically relevant concentrations of engineered (silica (SiO₂) and titanium dioxide (TiO₂) NPs) and environmental NPs (diesel exhaust particles, DEPs). This includes a multitude of secreted inflammatory, vascular, and endocrine placental factors as well as extracellular vesicle (EV)‐associated proteins. Moreover, conditioned media (CM) from NP‐exposed explants induce pronounced anti‐angiogenic and anti‐vasculogenic effects, while early neurodevelopmental processes are only marginally affected. These findings underscore the potential of metal oxide NPs and DEPs for widespread interference with the placental secretome and identify vascular morphogenesis as a sensitive outcome for the indirect developmental toxicity of different NPs. Overall, this work has profound implications for the future safety assessment of NPs for industrial, commercial, or medical applications in pregnancy, which should consider placenta‐mediated toxicity by holistic secretomics approaches to ensure the development of safe nanotechnologies.