Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy
Overview
Authors
Affiliations
Background: Current drugs used for osteoporosis therapy show strong adverse effects. Stem cell-derived extracellular vesicles (EVs) provide another choice for osteoporosis therapy. Mouse mesenchymal stem cells (mMSCs)-derived EVs promote bone regeneration; however, their clinical application is limited due to non-specific tissue targeting. Alendronate specifically targets bone tissue via hydroxyapatite. Therefore, EVs were combined with alendronate to generate Ale-EVs by "click chemistry" to facilitate EVs targeting bone via alendronate/hydroxyapatite binding.
Methods: Ale-EVs were characterized based on size using dynamic light scattering analysis and morphology was visualized by transmission electron microscopy. Hydroxyapatite affinity of Ale-EVs was detected by flow cytometry. Bone targeting of Ale-EVs was tested by ex vivo fluorescent imaging. Cell viability was assessed by using WST-8 reduction assay kit for testing the ability of Ale-EVs to promote mMSCs proliferation. Alkaline phosphatase experiment was used to detect ability of Ale-EVs to promote differentiation of mouse mesenchymal stem cells in vitro. Western blotting and Q-PCR assay were used to detect the early marker of osteogenic differentiation. Antiosteoporotic effects of Ale-EVs were detected in ovariectomy (OVX)-induced osteoporosis rat model. The safety of the Ale-EVs in vivo was measured by H&E staining and serum markers assay.
Results: In vitro, Ale-EVs had high affinity with hydroxyapatite. Also, ex vivo data indicated that Ale-EVs-DiD treatment of mice induced strong fluorescece in bone tissues compared with EVs-DiD group. Furthermore, results suggested that Ale-EVs promoted the growth and differentiation of mouse MSCs. They also protected against osteoporosis in ovariectomy (OVX)-induced osteoporotic rats. Ale-EVs were well tolerated and no side effects were found, indicating that Ale-EVs specifically target bone and can be used as a new therapeutic in osteoporosis treatment.
Conclusion: We used the Ale-N3 to modify mouse mesenchymal stem cells-derived extracellular vesicles by copper-free "click chemistry" to generate a Ale-EVs system. The Ale-EVs had a high affinity for bone and have great potential for clinical applications in osteoporosis therapy with low systemic toxicity.
Briffault E, Reyes R, Garcia-Garcia P, Rouco H, Diaz-Gomez L, Arnau M Int J Nanomedicine. 2024; 19:12171-12188.
PMID: 39588258 PMC: 11586229. DOI: 10.2147/IJN.S476546.
Huang Q, Jiang Y, Cao Y, Ding Y, Cai J, Yang T Regen Biomater. 2024; 11:rbae112.
PMID: 39323741 PMC: 11422186. DOI: 10.1093/rb/rbae112.
Harnessing exosomes for targeted therapy: strategy and application.
Ren X, Xu R, Xu C, Su J Biomater Transl. 2024; 5(1):46-58.
PMID: 39220669 PMC: 11362351. DOI: 10.12336/biomatertransl.2024.01.005.
Potential Targeting Mechanisms for Bone-Directed Therapies.
Celik B, Leal A, Tomatsu S Int J Mol Sci. 2024; 25(15).
PMID: 39125906 PMC: 11312506. DOI: 10.3390/ijms25158339.
Zhao Q, Feng J, Liu F, Liang Q, Xie M, Dong J Acta Pharm Sin B. 2024; 14(5):2210-2227.
PMID: 38799625 PMC: 11119514. DOI: 10.1016/j.apsb.2024.02.005.