Biotransformation of Atmospheric-Aged Metal-Sulfide Nanosheets in Respiratory Tract Fluids Potentiates Ferroptosis toward Alveolar Macrophages

The widespread application and unavoidable atmospheric release of transitional metal dichalcogenides (TMDCs) pose significant inhalation-related health risks. During respiration, atmospheric aging of nanoparticles occurs first; nonetheless, the hazard of air-aged TMDCs and the effect of postbiotransformation in the microenvironment following inhalation remain unclear. By mimicking atmospheric conditions and respiratory media, we discovered that air-aged molybdenum disulfide (A-MoS 2 ) and tungsten disulfide (A-WS 2 ) underwent biotransformation in artificial nasal fluids and Gamble’s solution, increasing the hydrophobicity and roughness of the nanosheets. The oxidized products (31.7% in A-MoS 2 and 44.5% in A-WS 2 ) were partially converted to sulfidation-state species via thiol-mediated reduction. Both biotransformed and air-aged TMDCs were localized to macrophage lysosomes at approximate concentrations, whereas the lysosomal membrane damage and ferrous ion (Fe 2+ ) release were more significant for biotransformed forms. Transcriptome and lipidomics analyses indicated that ferroprotein degradation and ferroportin1 inhibition also facilitated Fe 2+ overload, along with glutathione peroxidase 4 inhibition, lipid acylation, and phospholipid biosynthesis activation, worsening lipid peroxidation (154.3–225.6%). Shapley Additive Explanations substantiated the reduction of oxidized species, 1T-phase stabilization, and increased hydrophobicity as major contributors to ferroptosis aggravation of biotransformed TMDCs. Our findings highlight the necessity of incorporating biotransformation into risk assessment, rather than merely relying on the versions of nanomaterials following environmental processes as the testing endpoints.