Understanding the Molecular Toxicity of Metal-Based Nanoparticles Through Nanotoxicomics

Metal and metal oxide nanoparticles (NPs) are prevalent in industrial, medical, and consumer applications, yet concerns persist regarding their potential impact on human health. Traditional endpoint-based toxicological studies often face challenges in explaining the complex molecular mechanisms underlying the interactions between the physicochemical properties of NPs (eg, chemical composition, size, coating) and biological factors (eg, cell type). To address this gap, we introduce nanotoxicomics, a stepwise framework that integrates nanotoxicology with advanced omics technologies-transcriptomics, proteomics, and metabolomics. This approach enables multilevel analysis of NP effects, supporting the extrapolation of in vitro findings to tissues, organs, or whole systems. Moreover, this framework provides insights into the molecular mechanisms underlying consumer-product interactions and occupational exposure to NPs by enabling early detection of transcriptomic biomarkers, guiding downstream proteomic validation, and supplying metabolomic functional readouts that can be translated into potential clinical outcomes and enhanced risk assessment strategies. This review compiles and critically discusses evidence on the interactions of metal and metal oxide NPs with human cells and occupationally exposed populations. Key mechanisms include differential expression of genes related to oxidative stress, inflammation, and DNA damage (eg, SOD1, IL-6, MAP3K14, TP53), validation of protein biomarkers such as heat shock proteins and metallothioneins, and metabolite shifts reflecting ATP depletion, mitochondrial dysfunction, and redox imbalance (eg, GSH, PGE2, ATP). Finally, we highlight the value of nanotoxicomics and bioinformatics for designing safer NPs that can function as nanosensors, real-time monitoring agents, and drug delivery systems in nanomedicine, particularly in oncology, neurology, immunology, and cardiology. Overall, this study provides valuable insights into the molecular basis of metal and metal oxide nanoparticles and lays the groundwork for future research in predictive nanotoxicology, biomonitoring, and omics-driven risk assessment.