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

• Published in: Theranostics Vol. 12; no. 11; pp. 4866 - 4878
• Main Authors: Liang, Yujie, Xu, Xiao, Xu, Limei, Iqbal, Zoya, Ouyang, Kan, Zhang, Huawei, Wen, Chunyi, Duan, Li, Xia, Jiang
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2022; Ivyspring International Publisher
• Subjects: Animals; Arthritis; Cartilage; Cartilage, Articular - metabolism; Chondrocytes - metabolism; CRISPR; Dendritic cells; Disease; Exosomes - genetics; Exosomes - metabolism; Extracellular matrix; Gene Editing; Genetic engineering; Genome editing; Genomes; Genomics; Liposomes - metabolism; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Osteoarthritis; Osteoarthritis - metabolism; Peptides; Plasmids; Proteins; Rats; Research Paper; MMP-13; hybrid exosome; CRISPR/Cas9; Therapeutic genome editing; osteoarthritis; cartilage
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.69368

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. 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. 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 ( ), efficiently ablated the expression of in chondrocytes, and attenuated the hydrolytic degradation of the extracellular matrix proteins in the cartilage. Chondrocyte-specific knockdown of mitigates or prevents cartilage degradation in arthritic rats, showing that hybrid CAP-Exo/Cas9 sgMMP-13 may alleviate osteoarthritis.