Chondrocyte-specific genomic editing enabled by hybrid exosomes for osteoarthritis treatment

被引:115
作者
Liang, Yujie [1 ,2 ]
Xu, Xiao [1 ]
Xu, Limei [1 ]
Iqbal, Zoya [1 ]
Ouyang, Kan [1 ]
Zhang, Huawei [3 ]
Wen, Chunyi [4 ,5 ]
Duan, Li [1 ]
Xia, Jiang [2 ]
机构
[1] Shenzhen Univ, Shenzhen Peoples Hosp 2, Dept Orthoped, Affiliated Hosp 1, Shenzhen 518035, Peoples R China
[2] Chinese Univ Hong Kong, Dept Chem, Shatin, Hong Kong, Peoples R China
[3] South Univ Sci & Technol China, Dept Biomed Engn, Shenzhen 518055, Peoples R China
[4] Hong Kong Polytech Univ, Dept Biomed Engn, Hong Kong, Peoples R China
[5] Hong Kong Polytech Univ, Res Inst Smart Ageing, Hong Kong, Peoples R China
来源
THERANOSTICS | 2022年 / 12卷 / 11期
基金
中国博士后科学基金; 国家重点研发计划; 中国国家自然科学基金;
关键词
Therapeutic genome editing; hybrid exosome; CRISPR; Cas9; osteoarthritis; cartilage; MMP-13; DELIVERY; THERAPY; INJECTION; CRISPR; BRAIN;
D O I
10.7150/thno.69368
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Rationale: A cell-specific delivery vehicle is required to achieve gene editing of the disease-associated cells, so the hereditable genome editing reactions are confined within these cells without affecting healthy cells. A hybrid exosome-based nano-sized delivery vehicle derived by fusion of engineered exosomes and liposomes will be able to encapsulate and deliver CRISPR/Cas9 plasmids selectively to chondrocytes embedded in articular cartilage and attenuate the condition of cartilage damage. Methods: Chondrocyte-targeting exosomes (CAP-Exo) were constructed by genetically fusing a chondrocyte affinity peptide (CAP) at the N-terminus of the exosomal surface protein Lamp2b. Membrane fusion of the CAP-Exo with liposomes formed hybrid CAP-exosomes (hybrid CAP-Exo) which were used to encapsulate CRISPR/Cas9 plasmids. By intra-articular (IA) administration, hybrid CAP-Exo/Cas9 sgMMP-13 entered the chondrocytes of rats with cartilage damages that mimicked the condition of osteoarthritis. Results: The hybrid CAP-Exo entered the deep region of the cartilage matrix in arthritic rats on IA administration, delivered the plasmid Cas9 sgMMP-13 to chondrocytes, knocked down the matrix metalloproteinase 13 (MMP-13), efficiently ablated the expression of MMP-13 in chondrocytes, and attenuated the hydrolytic degradation of the extracellular matrix proteins in the cartilage. Conclusion: Chondrocyte-specific knockdown of MMP-13 mitigates or prevents cartilage degradation in arthritic rats, showing that hybrid CAP-Exo/Cas9 sgMMP-13 may alleviate osteoarthritis.
引用
收藏
页码:4866 / 4878
页数:13
相关论文
共 43 条
  • [1] Osteoarthritis Pathology, Diagnosis, and Treatment Options
    Abramoff, Benjamin
    Caldera, Franklin E.
    [J]. MEDICAL CLINICS OF NORTH AMERICA, 2020, 104 (02) : 293 - +
  • [2] Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
    Alvarez-Erviti, Lydia
    Seow, Yiqi
    Yin, HaiFang
    Betts, Corinne
    Lakhal, Samira
    Wood, Matthew J. A.
    [J]. NATURE BIOTECHNOLOGY, 2011, 29 (04) : 341 - U179
  • [3] [Anonymous], 2020, MED LETT DRUGS THER, V62, P57
  • [4] Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents
    Blanchard, Emmeline L.
    Vanover, Daryll
    Bawage, Swapnil Subhash
    Tiwari, Pooja Munnilal
    Rotolo, Laura
    Beyersdorf, Jared
    Peck, Hannah E.
    Bruno, Nicholas C.
    Hincapie, Robert
    Michel, Frank
    Murray, Jackelyn
    Sadhwani, Heena
    Vanderheyden, Bob
    Finn, M. G.
    Brinton, Margo A.
    Lafontaine, Eric R.
    Hogan, Robert J.
    Zurla, Chiara
    Santangelo, Philip J.
    [J]. NATURE BIOTECHNOLOGY, 2021, 39 (06) : 717 - 726
  • [5] Physical therapy in the management of frozen shoulder
    Chan, Hui Bin Yvonne
    Pua, Pek Ying
    How, Choon How
    [J]. SINGAPORE MEDICAL JOURNAL, 2017, 58 (12) : 685 - 689
  • [6] Cartilage-targeting and dual MMP-13/pH responsive theranostic nanoprobes for osteoarthritis imaging and precision therapy
    Chen, Haimin
    Qin, Zainen
    Zhao, Jinmin
    He, Yi
    Ren, En
    Zhu, Ye
    Liu, Gang
    Mao, Chuanbin
    Zheng, Li
    [J]. BIOMATERIALS, 2019, 225
  • [7] Genome Engineering for Osteoarthritis: From Designer Cells to Disease-Modifying Drugs
    Choi, Yun-Rak
    Collins, Kelsey H.
    Lee, Jin-Woo
    Kang, Ho-Jung
    Guilak, Farshid
    [J]. TISSUE ENGINEERING AND REGENERATIVE MEDICINE, 2019, 16 (04) : 335 - 343
  • [8] Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases
    Dabrowska, Magdalena
    Juzwa, Wojciech
    Krzyzosiak, Wlodzimierz J.
    Olejniczak, Marta
    [J]. FRONTIERS IN NEUROSCIENCE, 2018, 12
  • [9] A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties
    Dooley, Kevin
    McConnell, Russell E.
    Xu, Ke
    Lewis, Nuruddeen D.
    Haupt, Sonya
    Youniss, Madeleine R.
    Martin, Shelly
    Sia, Chang Ling
    McCoy, Christine
    Moniz, Raymond J.
    Burenkova, Olga
    Sanchez-Salazar, Jorge
    Jang, Su Chul
    Choi, Bryan
    Harrison, Rane A.
    Houde, Damian
    Burzyn, Dalia
    Leng, Charan
    Kirwin, Katherine
    Ross, Nikki L.
    Finn, Jonathan D.
    Gaidukov, Leonid
    Economides, Kyriakos D.
    Estes, Scott
    Thornton, James E.
    Kulman, John D.
    Sathyanarayanan, Sriram
    Williams, Douglas E.
    [J]. MOLECULAR THERAPY, 2021, 29 (05) : 1729 - 1743
  • [10] Exosomes as Targeted Delivery Platform of CRISPR/Cas9 for Therapeutic Genome Editing
    Duan, Li
    Ouyang, Kan
    Wang, Jianhong
    Xu, Limei
    Xu, Xiao
    Wen, Caining
    Xie, Yixin
    Liang, Yujie
    Xia, Jiang
    [J]. CHEMBIOCHEM, 2021, 22 (24) : 3360 - 3368