Extracellular vesicles derived from bone marrow mesenchymal stem cells loaded on magnetic nanoparticles delay the progression of diabetic osteoporosis via delivery of miR-150-5p

Abstract

Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) are emerged as carriers of therapeutic targets against bone disorders, yet its isolation and purification are limited with recent techniques. Magnetic nanoparticles (MNPs) can load EVs with a unique targeted drug delivery system. We constructed gold-coated magnetic nanoparticles (GMNPs) by decorating the surface of the Fe₃O₄@SiO₂ core and a silica shell with poly(ethylene glycol) (PEG)-aldehyde (CHO) and examined the role of BMSC-EVs loaded on GMNPs in diabetic osteoporosis (DO). The osteoporosis-related differentially expressed miR-150-5p was singled out by microarray analysis. DO models were then established in Sprague-Dawley rats by streptozotocin injection, where poor expression of miR-150-5p was validated in the bone tissues. Next, GMNP_E was prepared by combining GMNPs with anti-CD63, after which osteoblasts were co-cultured with the GMNP_E-BMSC-EVs. The re-expression of miR-150-5p facilitated osteogenesis in osteoblasts. GMNP_E could promote the enrichment of EVs in the bone tissues of DO rats. BMSC-EVs delivered miR-150-5p to osteoblasts, where miR-150-5p targeted MMP14 and consequently activated Wnt/β-catenin pathway. This effect contributed to the enhancement of osteoblast proliferation and maturation. Furthermore, GMNP_E enhanced the EV-based delivery of miR-150-5p to regulate the MMP14/Wnt/β-catenin axis, resulting in promotion of osteogenesis. Overall, our findings suggest the potential of GMNP-BMSC-EVs to strengthen osteoblast proliferation and maturation in DO, showing promise as an appealing drug delivery strategy against DO. 1. GMNPs-BMSCs-EVs-miR-150-5p promotes the osteogenesis of DO rats. 2. miR-150-5p induces osteoblast proliferation and maturation by targeting MMP14. 3. Inhibition of MMP14 activates Wnt/β-catenin and increases osteogenesis. 4. miR-150-5p activates the Wnt/β-catenin pathway by downregulating MMP14.

Keywords: Bone marrow mesenchymal stem cells; Diabetic osteoporosis; Extracellular vesicles; MMP14; Magnetic nanoparticles; MicroRNA-150-5p; Osteogenesis; Wnt/β-catenin pathway.