Understanding the underlying interaction between nanoparticle and organelles is conclusive to the nanotoxicology. According to existing literatures, lysosome is a crucial target of the nanoparticle carrier. Meanwhile, mitochondria could provide the essential energy for nanopaticles entering/exiting the cell. Based on the investigation of lysosome-mitochondria connection, we decoded the effects of low-dose ZIF-8 on energy metabolism, which are still largely obscure beforehand. In this research, low-dose ZIF-8 NPs were utilized to explore the effects on vascular endothelial cells, the first cells exposed to NPs during intravenous injection. Consequently, ZIF-8 could damage the energy metabolism, mainly manifested as mitochondrial fission, the decreased ATP production, and lysosomal dysfuction, which would subsequently affect the cell survival, proliferation and protein expression. This study highlights the fundamental understanding for exploring the regulation of nanoscale ZIF-8 in biological processes and its further application in biomedical field.