Silver nanoparticles (AgNPs) are widely used in industrial and biomedical applications due to their antimicrobial and anticancer properties. However, the molecular mechanisms underlying their cellular effects remain incompletely understood, limiting their safe implementation. Next-generation sequencing (NGS) enables high-throughput transcriptomic profiling, providing valuable insights into the cellular responses triggered by nanoparticle exposure. In this study, we evaluated the cytotoxic and transcriptomic effects of two polyvinylpyrrolidone (PVP)-stabilized AgNP formulations (AgNP1 and AgNP2) in human dermal fibroblasts (HDFa) and breast cancer cells (MCF7) across a range of concentrations (5–200 µg/mL). Cell viability assays indicated differential bioactivity to AgNP exposure depending on cell type and nanoparticle formulation. Comparative transcriptomic analysis revealed that both AgNP formulations disrupted cellular homeostasis through the dysregulation of pathways associated with protein folding, cytoskeletal organization, and endoplasmic reticulum function. Stress-related genes such as HSPA1A, HSPA1B, and HMOX1 were significantly upregulated following treatment. Overall, AgNP exposure induced cell type–dependent transcriptional responses, characterized by proteostasis-related stress pathways in HDFa cells and enhanced RNA processing and gene expression regulation in MCF7 cells. Gene Ontology enrichment analysis further highlighted alterations in biological processes related to protein refolding and cellular stress responses, as well as molecular functions associated with ATP-dependent protein-folding chaperones. Functional assays did not reveal significant increases in intracellular ROS levels or detectable apoptotic or necrotic cell death. Instead, the transcriptomic profiles suggest that AgNP exposure predominantly activates cellular stress responses associated with proteostasis and protein quality control. These findings provide new insights into the complex cellular responses triggered by PVP-stabilized AgNP formulations and highlight the importance of nanoparticle physicochemical properties and cell-type–dependent responses in determining biological outcomes. The results highlight the value of transcriptomic approaches to uncover early mechanistic responses to nanomaterials beyond conventional cytotoxicity endpoints.
González-Vega et al. (Wed,) studied this question.