Framework Nucleic Acid Nanoparticles Ameliorate Achilles TENDINOPATHY Through Tissue Penetration and Dual Regulation of the PI3K/AKT and MAPK Signaling Pathways

ABSTRACT The treatment of Achilles tendinopathy (AT) remains a challenge because of the poor drug penetration and abnormal accumulation of intracellular reactive oxygen species (ROS) caused by the dense tendon extracellular matrix (ECM) and hypovascularization. To address the aforementioned issues, we introduce tetrahedral framework nucleic acids (tFNAs) with excellent tissue penetration and ROS scavenging capability as a new therapeutic strategy for AT. First, we investigated the correlation between the permeability and the size of tFNAs in the Achilles tendons and found that among the three designed tFNA structures (TF13, TF21, and TF37), TF21 exhibited the strongest tendon penetration, and its penetration depth and infiltration volume in the AT tendons were significantly greater than those of ibuprofen (IBU), a commonly drug for AT treatment. Subsequently, TF21 showed significantly better therapeutic efficacy in improving locomotion, reducing collagen degradation, enhancing tendon mechanical properties, and ameliorating AT compared to IBU in AT rats. Finally, mechanistic studies indicated that TF21 rebalanced the anabolism and catabolism of AT tenocytes by eliminating intracellular ROS to simultaneously activate the PI3K/AKT and MAPK signaling pathways. Overall, TF21 demonstrates remarkable potential for the treatment of AT and may provide a promising paradigm for the application of the tFNA drugs in tendon diseases.