Engineered BMP2/BMP7 extracellular vesicles induce autocrine BMP release driving SMAD phosphorylation to promote bone formation

作者：Zeji Du, Skylar A. Rizzo, Tiffany L. Sarrafian, Monique S Bagwell, Ryan Mahlberg, Ashley Amontree, Paige Schiebel, Dinah M Tauferner, Zoe S LeBrasseur, Tyra A. Witt, Mary Nagel, Kyla Boyd, Humberto De Vitto, Matthew L. Hillestad, Paul G. Stalboerger, Matthew T. Houdek, Rafael J. Sierra, Atta Behfar · 发表于：npj Regenerative Medicine · 年份：2025 · DOI：10.1038/s41536-025-00405-2 · 被引用次数：15 · 研究领域：Extracellular vesicles in disease、Bone and Joint Diseases、MicroRNA in disease regulation

In the United States, impaired bone healing impacts ~600,000 patients annually. Bone morphogenetic protein 2 (rhBMP2) therapy is impeded by low bone quality and adverse effects. Here, mesenchymal stem cells, engineered to produce BMP2 and BMP2/7 containing extracellular vesicles (BMP2-EV and BMP2/7-EV), provided an alternative means of stimulating bone formation. BMP2-EV and BMP2/7-EV drove increased calcium deposition and alkaline phosphatase activity; with increase in osterix, RUNX2, osteocalcin, and osteopontin documenting osteoblast differentiation. BMP2/7-EV induced SMAD phosphorylation and calcium deposition, was inhibited by DMH1, a BMP I receptor inhibitor, demonstrating BMP receptor dependence. BMP2 and BMP7 extracellular vesicle encapsulation was confirmed with preserved potency following treatment with BMP antagonist, Noggin. Application of BMP2/7-EV in a rat calvarial defect model demonstrated enhanced bone formation on micro-computed tomography and histopathologic analysis, equaling rhBMP2. BMP2/7-EV mediated bone formation here highlights EVs as a unique modality for delivery of tailored polyvalent regenerative biotherapies.