Construction and anti-osteoporotic activity evaluation of dual-targeted exosomes derived from bone marrow mesenchymal stem cells.

Osteoporosis is a major public health concern worldwide, and mesenchymal stem cell (MSC)-derived exosomes hold promise as therapeutic agents and drug carriers for its treatment. However, the clinical translation of natural exosomes is limited by poor targeting and short retention. Here, we developed a bone/magnetic dual-targeted exosome delivery system (S-Z@ALN-SPIONs-EXO) by functionalizing BMSC-derived exosomes with alendronate (ALN) and superparamagnetic iron oxide nanoparticles (SPIONs) and co-loading them with danshensu and ZnO quantum dots. The system exhibited excellent biocompatibility, enhanced hydroxyapatite-binding affinity, and efficient BMSC uptake, significantly promoting osteogenic differentiation (increased ALP, OCN, and OPN) while suppressing osteoclast activity (reduced TRAP). In vivo fluorescence imaging revealed that S-Z@ALN-SPIONs-EXO achieved rapid and pronounced bone accumulation within 12 h post-injection, attributable to the synergistic actions of ALN-mediated bone targeting and SPION-facilitated magnetic retention. In the OVX osteoporotic mouse model, micro-CT and histological analyses confirmed substantial restoration of trabecular microarchitecture, increased collagen deposition, and marked inhibition of osteoclastogenesis, without detectable toxicity in major organs. This dual-targeted strategy outperformed single-modification systems, demonstrating its potential as an effective platform for osteoporosis therapy.