Imbalance of phosphoric acid homeostasis in alveolar macrophages mediates lung toxicity of rare earth oxide nanoparticles

Recent advancements in the application of rare earth elements (REEs) and the rapidly expanding field of nanotechnology have raised growing concerns over the potential health impacts associated with rare earth oxide nanoparticles (REO NPs). Despite an increasing interest, a comprehensive understanding of the toxicity of REO NPs remains elusive. While some REO NPs, such as La₂O₃ and CeO₂, have been shown to induce pulmonary injury to different degree, the mechanisms underlying these effects are not fully clear. In this study, we evaluated the cytotoxicity of sixteen REO NPs by CCK-8 assay in murine alveolar macrophages (MH-S), which revealed considerable heterogeneity (viability ranging from 34.7 % to 105.7 % at 50 μg/mL). Correlation analyses showed that the cytotoxicity was strongly associated with the capacity of REO NPs to adsorb phosphate and alter pH levels (R² = 0.37 and 0.56), whereas parameters such as hydrodynamic size, zeta (ζ)-potential, and extracellular release of RE ions did not correlate with cytotoxicity. Consistent with these findings, variations in intracellular phosphate depletion and lysosomal pH shifts were observed in MH-S. Moreover, phosphate starvation exacerbated cytotoxicity, while pre-treatment with phosphoric acid mitigated these effects. These findings were corroborated by in vivo test, which showed that REO NPs exhibiting higher reactivity with phosphoric acid also caused more severe lung damage, including impaired lung function and increased collagen deposition. Notably, phosphoric acid modification significantly alleviated lung injury. Collectively, these findings suggest that lung toxicity induced by REO NPs may be mediated by disruption of phosphoric acid homeostasis within macrophages, which offers critical insights into the mechanisms underlying the toxicity of REO NPs and potential health risks.