Tetrahedral framework nucleic acids loaded with resveratrol and TNF-α aptamer for the treatment of peripheral joint lesions in ankylosing spondylitis

Abstract Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease affecting the spine, sacroiliac and peripheral joints, with TNF-α as a core pro-inflammatory cytokine. Macrophages, as major TNF-α producers, form a positive feedback loop that amplifies local inflammatory responses. The use of clinical TNF inhibitors such as infliximab is limited by their high cost and high recurrence rate. This study constructs a targeted nano-delivery system named RSV@tFNAs-TNFαapt, by conjugating TNF-α aptamer to tetrahedral DNA nanostructures and loading resveratrol, a natural polyphenol with potent anti-inflammatory, antioxidant and immunomodulatory activities. The nanosystem showed uniform morphology, good stability and high cell uptake efficiency. In vitro, it promotes M2 macrophage polarization, inhibits pro-inflammatory and tissue-destruction-related factors, and reduced ROS production in synovial fibroblasts. In an AS rat model, it improves motor function, relieves joint swelling, alleviates spinal inflammation and structural damage, and reduces the production of peripheral inflammatory factors. Histopathology results confirms less inflammatory cell infiltration and protected cartilage and bone structure. In summary, RSV@tFNAs-TNFαapt exerts significant targeted anti-inflammatory and joint-protective effects, providing a complementary therapeutic strategy for AS, especially for peripheral joint lesions. Graphical abstract