Programmable peptide-DNA Origami nanocarriers enhancing cartilage retention for targeted gene silencing in osteoarthritis therapy

Osteoarthritis is a chronic degenerative joint disease marked by inflammatory and catabolic processes, particularly the overexpression of matrix metalloproteinase 13 (MMP13). RNA interference (RNAi) offers a promising strategy for targeted gene silencing, but is limited by rapid joint clearance and the dense, avascular cartilage extracellular matrix (ECM), which hinders siRNA penetration and retention. To address these barriers, we developed a cartilage-targeted siRNA delivery platform based on DNA origami, termed OWM, which is functionalized with the cartilage-binding peptide WYRGRL to enhance tissue specificity and retention, and loaded with siMMP13 to silence MMP13 expression. This system effectively delivered siMMP13 into chondrocytes, promoted endosomal escape, and significantly downregulated MMP13 expression. In addition, OWM reduced oxidative stress, restored anabolic gene expression, and suppressed catabolic activity. In vivo, it demonstrated prolonged joint retention, selective cartilage accumulation, minimal systemic distribution, and excellent biosafety. In a mouse model of OA, OWM treatment markedly attenuated cartilage degradation and synovial inflammation. These findings highlight the potential of OWM as a modular, biocompatible, and cartilage-specific nanoplatform for intra-articular gene therapy in OA and other joint disorders.