Nanotechnology has brought a rapid progress in the field of pharmacology and medicine. In particular, nanoparticles (NPs) have been extensively applied for targeted delivery system of contrast agents and drugs to fulfil more successful diagnosis and therapy of diseases. Many nanoparticles have been developed using various organic, inorganic and hybrid materials, and among them silica is one of attractive base materials in engineered nanoparticles. Silica nanoparticles (SiNPs) have been found considerable biomedical science, for such fields as biosensor, medical diagnostics, drug delivery, and cancer therapy. Although recent advances in potentials and risk assessment of SiNPs have been reported, the corresponding guideline to appropriate size and the toxic mechanisms of SiNPs have not been fully defined. To explore possible SiNPs-mediated cytotoxicity and determine size relevance, we fabricated SiNPs which enable facile control of their sizes: ‘seed’ SiNPs (20nm SiNPs; 22.98±0.66 nm) and ‘regrowth’ SiNPs (30,40,and 50nm SiNPs; 30.22±1.97, 40.91±2.88, and 48.84±1.22 nm. In a relative low range (< 25 μg/ml), even only 20nm SiNPs showed a significant decrease in cellular viability in a dose-dependent manner. Notably, they potently induced both apoptosis and necrosis, which was distinct mechanisms independently. First, exposure of the trace SiNPs increased ROS production at short time, and it was leading to direct influence on ER stress induction, supporting that the ROS-mediated ER stress is a crucial signaling in mitochondrial apoptosis pathway. Moreover, ROS significantly triggered increases in intracellular calcium ion (Ca2+) levels on ECs. Subsequently, 20nm SiNPs markedly induced autophagy through PI3K/Akt/eNOS signaling axis, and then autophagy induction triggered necrotomic cell death of ECs, indicating that SiNPs-induced cytotoxicity is associated with autophagy-mediated necrosis. In this study, we presented experimental data regarding the differential size-related biological effects of SiNPs on ECs. Although further investigations are required before the current findings can be clinically applied, these data will provide a better understanding of the mechanism underlying SiNPs size-dependent cytotoxicity in vasculature and facilitate the future development of safer biomedical applications of SiNPs
