Smaller-Sized Silica Nanoparticles Exacerbated Cardiomyocyte Pyroptosis by Impairing Mitophagy to Activate mtDNA-cGAS-STING Signaling

Silica nanoparticles (SiNPs) are a nanometer powder widely used in various consumer products, engineering, the food industry, and medical applications. Environmental SiNPs have attracted attention owing to their exposure to various cardiovascular adverse events. Here, we exposed C57/BL6 mouse and HL-1 cells with different-sized SiNPs (50, 300 nm, and 1 μm) to investigate the underlying mechanism of its cardiovascular toxicity. Mice exposed to three-sized SiNPs showed significant weight loss after 21 days of treatment. Heart weight to tibia length ratio and histopathology staining indicated increased heart volume and cross-sectional area of myocardial fibers in mice exposed to SiNPs. In vivo and in vitro experiments results showed that exposure to SiNPs causes size-dependent mitochondrial damage and initiates mitophagy. Notably, compared to the damage caused by 300 nm and 1 μm SiNPs exposure, 50 nm SiNPs blocked autophagy flux, leading to excessive accumulation of mitochondrial DNA (mtDNA) in the cytoplasm, ultimately exacerbating downstream cGAS-STING pathway-mediated pyroptosis. This study revealed the potential health risks of SiNPs and helped to understand the differences in cytotoxicity caused by SiNPs of different sizes.