Biomimetic Extracellular Vesicles Based on Composite Bioactive Ions for the Treatment of Ischemic Bone Disease

Extracellular vesicles (EVs) have demonstrated considerable potential in the treatment of ischemic bone diseases, such as glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). However, the clinical application of EVs faces challenges such as low yield, poor bioactivity, and lack of targeting. Herein, we have developed a platform of multiengineered extracellular vesicle mimetics (EVMs) to address these challenges. By stimulating mesenchymal stem cells (MSCs) with multibioactive ions from TS (Trisilicate, a mixture of calcium silicate, magnesium silicate, and strontium silicate), we obtained endogenously modified TS-MSCs. From these, we further prepared a large quantity of bioactive EVM_TS-MSCs through a straightforward extrusion method. Moreover, by integrating metabolic glycoengineering with click chemistry strategies, alendronate (ALN) was surface-modified on EVM_TS-MSCs to further prepare ALN-EVM_TS-MSCs. The engineered ALN-EVM_TS-MSCs demonstrated bone-targeting effects, promoting osteogenesis and angiogenesis. This promoting effect is attributed to the rich presence of miR-21 in the TS-modified EVM, which further silences PTEN to activate the PI3K/AKT signaling pathway, thereby enhancing osteogenesis and angiogenesis. Our treatment strategy for ischemic bone diseases is based on a multiengineered, biomaterial-inspired, metabolic glycoengineering, and click chemistry-based platform of EVM. This study also provides an enhanced understanding of the development and application of engineered vesicles in disease treatment.