Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss

Abstract The differentiation shift from osteogenesis to adipogenesis of bone marrow mesenchymal stem cells (BMSCs) characterizes many pathological bone loss conditions. Stromal cell-derived factor-1 (SDF1) is highly enriched in the bone marrow for C-X-C motif chemokine receptor 4 (CXCR4)-positive hematopoietic stem cell (HSC) homing and tumor bone metastasis. In this study, we displayed CXCR4 on the surface of exosomes derived from genetically engineered NIH-3T3 cells. CXCR4+ exosomes selectively accumulated in the bone marrow. Then, we fused CXCR4+ exosomes with liposomes carrying antagomir-188 to produce hybrid nanoparticles (NPs). The hybrid NPs specifically gathered in the bone marrow and released antagomir-188, which promoted osteogenesis and inhibited adipogenesis of BMSCs and thereby reversed age-related trabecular bone loss and decreased cortical bone porosity in mice. Taken together, this study presents a novel way to obtain bone-targeted exosomes via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss.