Immune-driven biotransformation of gold nanosheets by human primary neutrophils.

The presumed chemical inertness of gold nanomaterials underpins their biomedical application, yet their structural fate within the oxidative milieu of innate immune cells remains uncharacterised. Here, we show that sustained engagement of two-dimensional gold nanosheets (AuNS) with primary human neutrophils over 14 days induces progressive crystalline domain disruption and sulfur incorporation within degraded regions, resolved by transmission and scanning electron microscopy with coupled energy-dispersive X-ray analysis. Pharmacological dissection using inhibitors of myeloperoxidase (4-aminobenzoic acid hydrazide, 4-ABAH), NADPH oxidase NOX1/4 (Setanaxib; GKT137831) and 1-methylpropyl 2-imidazolyl disulfide; thioredoxin-1 (PX12) demonstrates that degradation requires convergence of parallel oxidative routes (MPO/HOCl and Fenton-like) with Trx-1-mediated thiol capture of Au+ as Au-S-Trx. PX12 abolishes the diagnostic Au-S signature without restoring gold content, whereas simultaneous blockade of all three axes returns gold to near-pristine levels with near-complete nanosheet persistence. Transcriptional profiling further reveals coupling between oxidative burst activity and inflammatory signalling. These findings redefine the biological stability of gold nanostructures under physiologically relevant inflammatory conditions.