Nanotherapy for bone repair: milk-derived small extracellular vesicles delivery of icariin

Abstract

Icariin (ICA) played an important role in the treatment of inflammatory bone defects. However, pharmacokinetic studies have shown that its poor bioavailability limited its application. In this context, we isolated bovine milk-derived sEV and prepared sEV-ICA to improve the osteogenic effect of ICA. In this study, we successfully constructed sEV-ICA. sEV-ICA was found to have significantly higher osteogenic efficiency than ICA in cell culture and cranial bone defect models. Mechanistically, bioinformatics analysis predicted that signal transducers and activators of transcription 5 (STAT5a) may bind to the GJA1 promoter, while luciferase activity assays and chromatin immunoprecipitation (ChIP) experiments confirmed that STAT5a directly binded to the GJA1 promoter to promote osteogenesis. We proved that compared with ICA, sEV-ICA showed a better effect of promoting bone repair in vivo and in vitro. In addition, sEV-ICA could promote osteogenesis by promoting the combination of STAT5a and GJA1 promoter. In summary, as a complex drug delivery system, sEV-ICA constituted a rapid and effective method for the treatment of bone defects and could improve the osteogenic activity of ICA.

Keywords:

• Bone remodeling
• icariin
• milk
• small extracellular vesicles
• nanotherapy

Acknowledgements

The authors gratefully acknowledge the time and energy spent by the study participants.

Authors’ contributions

Weidong Niu, Tingjiao Liu, Ying Kong, Xinxin Yu, and Ming Dong were responsible for study concept and design. Xinxin Yu and Ming Dong were responsible for data analysis and drafting of the manuscript. Qian Yang, Long Wang, Wenqing Han, and Juhong Dong were responsible for the acquisition and analysis of the data. Lina Wang provided the technical and material support. Weidong Niu, Tingjiao Liu, and Ying Kong were responsible for study supervision.

Disclosure statement

The authors declare that they have no competing interests.

Ethical approval statement

Ethical approval to conduct the study was obtained from the Ethical Committee of School of Stomatology, Dalian Medical University (2021006).

Data availability statement

The transcriptome-sequencing data is available from Sequence Read Archive (http://www.ncbi.nlm.nih.gov/bioproject/836700).

Additional information

Funding

This work was supported by the Science and Technology Plan of Liaoning Province (2021JH2/10300027); National Natural Science Foundation of China (82270971; 82100998); Liaoning Province Doctor Startup Fund Funded (2022-BS-237); Dalian Science and Technology Innovation Fund (2022JJ13SN063).