Nano-bio interaction determines the early progression of lung cancer by reshaping pulmonary epithelial microenvironment.

While the pulmonary microenvironment is a complex ecosystem comprising lung epithelial cells, immune cells, interstitial cells, and blood vessels, this study specifically focuses on the epithelium-centric niche to investigate the specific effects of SiNPs. This targeted microenvironment, centered on the interaction between epithelial components and their immediate surroundings, is intricately linked to the early progression and progression of lung cancer. Due to the prominent advances in nanotechnology recently, the interactions between nanoparticles and humans are inevitable. However, the role and precise mechanism of nano-bio interactions in PEM and their contributions to lung cancer are yet to be elucidated. In this study, we unexpectedly discovered that pulmonary exposure to silicon nanoparticles (SiNPs), a significant inhaled pollutant nanoparticle which was previously involved in inflammatory and fibrosis responses in the lung, intriguingly inhibited the early progression and metastasis of lung cancer in both in vitro and in vivo models. Mechanistically, SiNPs disrupted lysosomal function in lung epithelial cells, impaired the autophagosome-lysosome degradation pathway, and reduced Extracellular vesicles (EVs)-mediated communication between lung epithelial cells and lung cancer cells. An obvious decrease in EVs and their cargo, particularly miR-296-3p, within the tumor microenvironment heightened the susceptibility of lung cancer cells to ferroptosis. Our findings suggest that pulmonary exposure to SiNPs inhibits lung cancer early progression and metastasis, with the Atg5/EVs/miR-296-3p axis playing a critical role in this process. This study offers new insights into the mechanisms linking nano-bio interaction reshaped pulmonary epithelial microenvironment and lung cancer progression.