Simvastatin-enhanced bioinspired exosome mimetics regulate osteogenesis and angiogenesis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head

•Bioinspired EM from SIM-pretreatment MSCs improves GIONFH treatment.•SIM-MSCs-EM exhibits better osteogenesis and angiogenesis ability than MSCs-EM.•SIM-MSCs-EM delivers miR-29b-3p to silence PTEN and activate PI3K/AKT pathway. Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive glucocorticoid use. Promoting osteogenesis and angiogenesis simultaneously is the key to prevent or treat GIONFH at early stage. Recently, exosomes secreted by mesenchymal stem cells (MSCs) have played a significant role in preventing GIONFH by enhancing osteogenesis and angiogenesis. However, poor yield, difficulty in purification and unpredictable therapeutic effect of exosomes have been obstacles for widespread use in clinical practices. Here, this study reported bioinspired exosome mimetics (EM) derived from simvastatin (SIM)-pretreatment MSCs (SIM-MSCs-EM) by an extrusion approach. Our results demonstrated SIM-MSCs-EM exhibited better osteogenesis and angiogenesis ability compared to EM derived from MSCs (MSCs-EM), alleviating the progression of GIONFH in vivo. Due to the unique endogenous miRNA cargos, SIM-MSCs-EM deliver miR-29b-3p to silence the target gene phosphatase and tensin homolog (PTEN) and then activate the PI3K/AKT pathway, which exerts a vital role in osteogenesis and angiogenesis. Taken together, our study proposed that SIM-enhanced bioinspired EM could be a feasible approach by regulating osteogenesis and angiogenesis for the treatment of GIONFH and other avascular osteonecrosis disease.