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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\u2010Curcumin (tFNAs\u2010Cur) as a novel therapeutic for PH, targeting multiple synergistic pathways including TGF \u03b21, NF\u2010\u03baB, and PI3K\u2010Akt. The proposed tFNAs\u2010Cur featured the advantages of high drug loading capacity, good water solubility, strong stability, and excellent biocompatibility. Cellular experiments demonstrate that tFNAs\u2010Cur is efficiently internalized by pulmonary artery smooth muscle cells, alleviates oxidative stress, and inhibits their proliferation and migration. In the monocrotaline\u2010induced PH rat model, tFNAs\u2010Cur 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\u2010Cur were mediated via the ROS\/TGF \u03b21 antioxidant, NF\u2010\u03baB anti\u2010inflammatory, and PI3K\u2010Akt anti\u2010proliferative pathways. The proposed tFNAs\u2010Cur provides an efficient and safe method with potential for clinical translation that simultaneously utilizes multiple synergistic mechanisms for the treatment of PH.<\/jats:p>","DOI":"10.1002\/adhm.202505281","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T07:17:15Z","timestamp":1768375035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Curcumin\u2010Loaded Tetrahedral Framework Nucleic Acids Alleviate Pulmonary Hypertension by Regulating Multiple Synergistic Signaling Pathways"],"prefix":"10.1002","volume":"15","author":[{"given":"Xiaomeng","family":"Yue","sequence":"first","affiliation":[{"name":"Department of Radiology Tianjin Medical University General Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics College of Artificial Intelligence Medicine Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology Tianjin Medical University General Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liujie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiology Tianjin Medical University General Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Diagnosis and Treatment National Clinical Research Center for Cancer Tianjin's Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and Therapy Tianjin Medical University Cancer Institute and Hospital  Tianjin 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