Chondrocyte-Targeted Delivery System of Sortase A-engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy.

Targeted drug delivery and the reduction of off-target effects are crucial for the promising clinical application of nucleic acid drugs. To address this challenge, we developed a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase-13 (ASO-MMP13) to chondrocytes. Small extracellular vesicles (exos) were ligated with chondrocyte affinity peptide (CAP) using Sortase A and subsequently incubated with cholesterol-modified ASO-MMP13 to construct a chondrocyte-targeted drug delivery exo (CAP-exoASO). Compared with exos without CAP (ExoASO), CAP-exoASOs attenuated IL-1β-induced chondrocyte damage and prolonged the retention time of ASO-MMP13 in the joint without distribution in major organs following intra-articular injection. Notably, CAP-exoASOs decreased MMP13 expression (P < 0.001) and upregulated COL2A1 expression (P = 0.006), resulting in reorganization of the cartilage matrix and alleviation of progression in the OA model. Furthermore, the Osteoarthritis Research Society International score of articular cartilage tissues treated with CAP-exoASO was comparable with that of healthy rats (P = 0.148). A mechanistic study demonstrated that CAP-exoASO may reduce inflammation by suppressing the IL-17 and TNF signaling pathways. Based on the targeted delivery effect, CAP-exoASOs successfully accomplished cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy. This article is protected by copyright. All rights reserved.