title: A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts.
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 in vivo, 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.
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dang
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, 721000, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liang
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: He
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Wu
authors.affiliation: Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, 721000, China.
authors.forename: Airong
authors.initials: A
authors.lastname: Qian
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, 999077, Hong Kong, China.
authors.forename: Doris W T
authors.initials: DW
authors.lastname: Au
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, 999077, Hong Kong, China.
authors.forename: Michael W L
authors.initials: MW
authors.lastname: Chiang
authors.affiliation: School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China.
authors.forename: Bao-Ting
authors.initials: BT
authors.lastname: Zhang
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Quanbin
authors.initials: Q
authors.lastname: Han
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Kevin K M
authors.initials: KK
authors.lastname: Yue
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Lv
authors.affiliation: Department of Orthopaedics & Traumatology, Shenzhen People's Hospital, Second Medical College of Ji'nan University, Shenzhen, 518020, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Pan
authors.affiliation: Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA 6009, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Zhaoxiang
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, 721000, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Shang
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, FA 32611-7200, USA; Department of Physiology and Functional Genomics, University of Florida, Gainesville, FA 32611-7200, USA; Center for Research at Bio/Nano Interface, Shands Cancer Center, University of Florida, Gainesville, FA 32611-7200, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Tan
authors.affiliation: Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Institute of Molecular Medicine, Peking University, Beijing, 100871, China.
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, 721000, China. Electronic address: borisguo@hkbu.edu.hk.
authors.forename: Baosheng
authors.initials: B
authors.lastname: Guo
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China; Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China. Electronic address: aipinglu@hkbu.edu.hk.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China; Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone & Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu 215347, China; Institute of Integrated Bioinformatic Medicine and Translational Sciences, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen 518057, China; Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, 518057, China; Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Science, Northwestern Polytechnical University, Xi'an, 721000, China. Electronic address: zhangge@hkbu.edu.hk.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation / Q000187:drug effects*; D016503:Drug Delivery Systems; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008081:Liposomes; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D009841:Oligonucleotides; D010455:Peptides
keywords: Bone resorption; MicroRNA; Osteoclast; Targeted delivery system