Chondrocyte‐Targeted Delivery System of Sortase A‐Engineered Extracellular Vesicles Silencing MMP13 for Osteoarthritis Therapy

Abstract 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, a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase‐13 (ASO‐MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) are 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 attenuate IL‐1β‐induced chondrocyte damage and prolong the retention time of ASO‐MMP13 in the joint without distribution in major organs following intra‐articular injection. Notably, CAP‐exoASOs decrease MMP13 expression ( P < 0.001) and upregulate 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 (OARSI) score of articular cartilage tissues treated with CAP‐exoASO is comparable with that of healthy rats ( P = 0.148). A mechanistic study demonstrates that CAP‐exoASO may reduce inflammation by suppressing the IL‐17 and TNF signaling pathways. Based on the targeted delivery effect, CAP‐exoASOs successfully accomplish cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy.