A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts

Jin Liu, Lei Dang, Defang Li, Chao Liang, Xiaojuan He, Heng Wu, Airong Qian, Zhijun Yang, Doris W.T. Au, Michael W.L. Chiang, Bao Ting Zhang, Simon Q B Han, Kevin K M Yue, Hong Qi Zhang, Changwei Lv, Xiaohua Pan, Jiake Xu, Zhaoxiang Bian, Peng Shang, Weihong TanZicai Liang, Baosheng Guo*, Aiping Lyu, Ge Zhang

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

85 Citations (Scopus)

Abstract

Dysregulated microRNAs in osteoclasts could cause many skeletal diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNAs modulators targeting osteoclasts with minimal off-target effects. Bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts. Considering that the eight repeating sequences of aspartate (D-Asp8) could preferably bind to highly crystallized hydroxyapatite, we developed a targeting system by conjugating D-Asp8 peptide with liposome for delivering microRNA modulators specifically to bone resorption surfaces and subsequently encapsulated antagomir-148a (a microRNA modulator suppressing the osteoclastogenic miR-148a), i.e. (D-Asp8)-liposome-antagomir-148a. Our results demonstrated that D-Asp8 could facilitate the enrichment of antagomir-148a and the subsequent down-regulation of miR-148a in osteoclasts invivo, resulting in reduced bone resorption and attenuated deterioration of trabecular architecture in osteoporotic mice. Mechanistically, the osteoclast-targeted delivery depended on the interaction between bone resorption surfaces and D-Asp8. No detectable liver and kidney toxicity was found in mice after single/multiple dose(s) treatment of (D-Asp8)-liposome-antagomir-148a. These results indicated that (D-Asp8)-liposome as a promising osteoclast-targeting delivery system could facilitate clinical translation of microRNA modulators in treating those osteoclast-dysfunction-induced skeletal diseases.

Original languageEnglish
Pages (from-to)148-160
Number of pages13
JournalBiomaterials
Volume52
Issue number1
DOIs
Publication statusPublished - Jun 2015

Scopus Subject Areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

User-Defined Keywords

  • Bone resorption
  • MicroRNA
  • Osteoclast
  • Targeted delivery system

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