Inhalation of Environmentally Simulated PET Nanoplastics Induces Demyelinating Disorders via the CXCL12/CXCR4 Axis.

The health threat from airborne nanoplastics (NPs) remains unclear, as despite inhalation being a more direct brain entry route than ingestion, current understanding relies on oral exposure and commercial particle models that obscure realistic risks. Here, by integrating environmentally simulated polyethylene terephthalate (PET)-NPs with an aerosol inhalation model that mirrors real-world human exposure (0.1, 1, and 10 mg/m3), we demonstrate that chronic NP inhalation translocated to the brain and induced demyelination, neuroinflammation, and cognitive deficits. The most pronounced effects were observed at the highest exposure dose (10 mg/m3), which is relevant to the occupational settings. Mechanistically, NP exposure triggered astrocytic CXCL12 release, leading to CXCR4-dependent microglial activation and cytokine network dysregulation. In vitro, blockade of CXCR4 with AMD3100 attenuated NP-induced microglial migration and oligodendrocytic myelin basic protein reduction. Our study thus definitively links realistic airborne NP exposure to the key neuropathological features of demyelinating disorders and pinpoints a modifiable molecular pathway that could inform exposure-based preventive strategies. These findings underscore the need for further assessment of airborne NP risks, particularly in occupational settings.