Bone-targeting Engineered Milk-derived Extracellular Vesicles for MRI-assisted Therapy of Osteoporosis

Abstract The imbalance between osteoblasts and osteoclasts is the cause of osteoporosis. Milk-derived extracellular vesicles (mEVs), excellent drug delivery nanocarriers, can promote bone formation and inhibit bone resorption. In this study, we conjugated bone-targeting peptide (AspSerSer, DSS)6 to mEVs by click chemistry and then loaded with SRT2104, a SIRT1 (silent mating-type information regulation 2 homolog 1) agonist that was proofed to help reduce bone loss. The engineered (DSS)6-mEV-SRT2104 had the intrinsic anti-osteoporosis function of mEVs and SRT2104 to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis. Furthermore, we labelled mEVs with MnB nanoparticles that can be used for the in vivo magnetic resonance imaging (MRI) visualization. The obtained nanocomposites significantly prevented bone loss in osteoporosis mice and increased bone mineral density, exhibiting superior bone accumulation under MRI. We believe the proposed (DSS)6-mEV-SRT2104/MnB provides a novel paradigm for osteoporosis treatment and monitoring.