Size- and morphology-dependent cytotoxicity of metal-organic frameworks: Deciphering the structure-toxicity...

Metal-organic frameworks (MOFs), as an emerging nanomaterial, have been widely used in the field of biomedicine due to their excellent loading performance. However, the unclear synergistic biological toxicity associated with variations in the morphology and particle size of nano-MOFs hinder their broader development. In this work, we prepared four kinds of nano-MOFs, which showed significant differences in cytotoxicity to human embryonic kidney 293 cells (HEK293) and human hepatocellular carcinomas (HepG2) due to their different particle sizes and morphologies. Uptake pathway analysis showed that the macropinocytosis pathway was more easily activated in HEK293 cells to engulf nano-sized particles, while clathrin-mediated endocytosis was more likely to encapsulate small-sized nanoparticles (NPs). In general, at low concentrations of NPs exposure, ZIF-67s had higher or similar cell damage than ZIF-8s, while at high concentrations, the overall toxicity of ZIF-8s was stronger than that of ZIF-67s; the larger size of ZIFs is more likely to lead to higher cell death rate; the cubic morphology ZIF-67s showed stronger biocompatibility to HEK293 cells than the dodecahedron. These findings establish a theoretical foundation for assessing the environmental health risks of MOFs and guaranteeing their safe application, providing valuable guidance for the subsequent design and development of biocompatible materials.