Nanoscale Zeolitic Imidazolate Framework-8 Activator of Canonical MAPK Signaling for Bone Repair

Zeolitic imidazolate framework-8 (ZIF-8) is an important type of metal organic framework and has found numerous applications in the biomedical field. Our previous studies have demonstrated that nano ZIF-8-based titanium implants could promote osseointegration; however, its osteogenic capacity and the related mechanisms in bone regeneration have not been fully clarified. Presented here is a nanoscale ZIF-8 that could drive rat bone mesenchymal stem cell (rBMSC) differentiation into osteoblasts both in vitro and in vivo, and interestingly, nano ZIF-8 exhibited a better osteogenic effect compared with ionic conditions of Zn at the same concentration of Zn²⁺. Moreover, the cellular uptake mechanisms of the nanoparticles were thoroughly clarified. Specifically, nano ZIF-8 could enter the rBMSC cytoplasm probably via caveolae-mediated endocytosis and macropinocytosis. The intracellular and extracellular Zn²⁺ released from nano ZIF-8 and the receptors involved in the endocytosis may play a role in inducing activation of key osteogenic pathways. Furthermore, through transcriptome sequencing, multiple osteogenic pathways were found to be upregulated, among which nano ZIF-8 primarily phosphorylated ERK, thus activating the canonical mitogen-activated protein kinase pathway and promoting the osteogenesis of rBMSCs. Taken together, this study helps to elucidate the mechanism by which nano ZIF-8 regulates osteogenesis and suggests it to be a potential biomaterial for constructing multifunctional composites in bone tissue engineering.