Amelioration of Osteoarthritis via Tetrahedral Framework Nucleic Acids Delivering Microrna‐124 for Cartilage Regeneration

Abstract MicroRNAs (miRNAs) regulate several physiological and pathological processes involved in various diseases, including osteoarthritis (OA). OA is the most common global musculoskeletal disorder, characterized by the irreversible progressive destruction of articular cartilage. Supplementation with exogenous miRNAs may represent a promising therapeutic OA treatment, with miRNA‐124 (miR‐124) being a prime candidate for its anti‐inflammatory ability; however, an effective drug delivery system is urgently required to enhance miR‐124 stability and capacity to enter chondrocytes. To this end, tetrahedral framework nucleic acids’ (tFNAs) self‐assembled 3D DNA nanostructures possess superior inherent biocompatibility, versatile functionality, unsurpassed editability, and strong cellular internalization ability. In this study, tFNAs carrying one or three miR‐124 (T‐miR1 or T‐miR3) are successfully synthesized. T‐miR3 is largely absorbed via induced inflammatory chondrocytes by IL‐1β. With reactive oxygen species’ scavenging ability and inflammation‐suppressive miR‐124 release behavior, T‐miR3 efficiently protects chondrocytes against IL‐1β injury in vitro. Additionally, T‐miR3 effectively prevents OA progression by inhibiting chondrocyte apoptosis, smoothing cartilage surfaces, suppressing extracellular matrix degradation, and increasing synovial thickness, effectively protecting in vivo articular cartilage, and illustrating the therapeutic ability of T‐miR3 in OA treatment. This study provides experimental evidence and novel therapeutic strategies for OA treatment in the clinical setting.