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 EVMTS-MSCs through a straightforward extrusion method. Moreover, by integrating metabolic glycoengineering with click chemistry strategies, alendronate (ALN) was surface-modified on EVMTS-MSCs to further prepare ALN-EVMTS-MSCs. The engineered ALN-EVMTS-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.
Keywords: bioactive ions; bone targeted delivery; extracellular vesicle mimetics; ischemic bone diseases; miR-21.