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Theranostics 2022; 12(11):4866-4878. doi:10.7150/thno.69368 This issue Cite

Research Paper

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

Yujie Liang^1,2*, Xiao Xu^1*, Limei Xu^1*, Zoya Iqbal¹, Kan Ouyang¹, Huawei Zhang³, Chunyi Wen^4,5, Li Duan^1✉, Jiang Xia^2✉

1. Department of Orthopedics, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China.
2. Department of Chemistry, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
3. Department of Biomedical Engineering, South University of Science and Technology of China, Shenzhen, 518055, China.
4. Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China.
5. Research Institute of Smart Ageing, The Hong Kong Polytechnic University, Hong Kong SAR, China.
*These authors contributed equally to this work.

✉ Corresponding authors: E-mail: jiangxiaedu.hk (J.X.); duanledu.cn (L.D.).

Abstract

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.

Keywords: Therapeutic genome editing, hybrid exosome, CRISPR/Cas9, osteoarthritis, cartilage, MMP-13

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