Efficient Delivery\nof siRNA via Tetrahedral Framework\nNucleic Acids: Inflammation Attenuation and Matrix Regeneration in\nTemporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is the\nmost common\nand severe subtype of temporomandibular disease characterized by inflammation\nand cartilage matrix degradation. Compared with traditional conservative\ntreatment, small interfering RNAs (siRNAs) have emerged as a more\nefficient gene-targeted therapeutic tool for TMJOA treatment. Nuclear\nfactor kappaB (NF-κB) is a transcription factor orchestrating\nthe inflammatory processes in the pathogenesis of TMJOA. Employing\nsiRNA-NF-κB could theoretically control the development of TMJOA.\nHowever, the clinical applications of siRNA-NF-κB are limited\nby its structural instability, poor cellular uptake, and short TMJ\nretention. To overcome these shortcomings, we developed a tetrahedral\nframework nucleic acid (tFNA) system carrying siRNA-NF-κB, named\nTsi. The results indicated that Tsi exhibited excellent structural\nstability and excellent cellular uptake efficiency. It also demonstrated\na superior NF-κB silencing effect over siRNA alone, attenuating\nthe activation of NF-κB and upregulating the NRF2/HO-1 pathway.\nThis system effectively reduced the release of inflammatory factors\nand reactive oxygen species (ROS), inhibiting cellular oxidative stress\nand apoptosis. <i>In vivo</i>, Tsi displayed enhanced TMJ\nretention capacity in comparison to siRNA alone and offered significant\nprotective effects on both the cartilage matrix and subchondral bone,\npresenting a promising approach for TMJOA treatment.