Curcumin‐Loaded Tetrahedral Framework Nucleic Acids Alleviate Pulmonary Hypertension by Regulating Multiple Synergistic Signaling Pathways

Pulmonary hypertension (PH) is a severe pulmonary vascular disease that ultimately leads to right heart failure, which involves multiple core mechanisms, including oxidative stress, inflammation, and pathological cellular proliferation. However, current therapies are limited in simultaneously modulating multiple core mechanisms, leading to poor clinical outcomes and high mortality. Herein, we introduce tetrahedral framework nucleic acids-Curcumin (tFNAs-Cur) as a novel therapeutic for PH, targeting multiple synergistic pathways including TGF β1, NF-κB, and PI3K-Akt. The proposed tFNAs-Cur featured the advantages of high drug loading capacity, good water solubility, strong stability, and excellent biocompatibility. Cellular experiments demonstrate that tFNAs-Cur is efficiently internalized by pulmonary artery smooth muscle cells, alleviates oxidative stress, and inhibits their proliferation and migration. In the monocrotaline-induced PH rat model, tFNAs-Cur significantly improves pulmonary artery acceleration time, reduces vascular wall thickness, and medial pulmonary artery diameter. Cardiac assessments show improved exercise capacity, reduced Fulton index, and alleviated right ventricular fibrosis. Further transcriptomic and biochemical analyses reveal that the therapeutic effects of tFNAs-Cur were mediated via the ROS/TGF β1 antioxidant, NF-κB anti-inflammatory, and PI3K-Akt anti-proliferative pathways. The proposed tFNAs-Cur provides an efficient and safe method with potential for clinical translation that simultaneously utilizes multiple synergistic mechanisms for the treatment of PH.