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Unfortunately, effective and safe treatments remain strikingly deficient across basic research and clinical applications. Tetrahedral framework nucleic acids (tFNAs), with superior biocompatibility and versatile cellular regulatory capabilities, offer a promising therapeutic strategy for PH. Herein, a novel strategy for treating PH using tFNAs by regulating calcium homeostasis is presented. The synthesized tFNAs, which display ultra\u2010small size, robust stability, and good biocompatibility, exhibit enhanced cellular uptake in pulmonary artery smooth muscle cells and markedly suppress their proliferation and migration. In the PH model, pulmonary arterial (PA) structural\u2010functional analysis reveals that tFNAs significantly improve pulmonary artery acceleration time, reduce vascular wall thickness, and decrease \u03b1\u2010SMA and PCNA expression. Cardiac structural\u2010functional assessments, including treadmill tests, Sirius Red staining, and Masson's trichrome staining, show that tFNAs remarkably enhance exercise capacity, reduce the Fulton index, and alleviate right ventricular (RV) fibrosis. Transcriptomic and biochemical analyses reveal that tFNAs upregulate SERCA2a, downregulate VEGFD, restore calcium homeostasis, and modulate the PI3K\u2010Akt pathway, thus ameliorating PA and RV remodeling. This study presents a novel DNA nanomaterial\u2010based strategy for PH treatment and establishes a mechanistic foundation for future clinical applications.<\/jats:p>","DOI":"10.1002\/adhm.202502810","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T10:26:59Z","timestamp":1754908019000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Self\u2010Assembled Tetrahedral Framework Nucleic Acids Alleviate Pulmonary Hypertension by Regulating Calcium Homeostasis"],"prefix":"10.1002","volume":"14","author":[{"given":"Lin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Radiology Tianjin Medical University General Hospital Tianjin Medical University  Tianjin 300052 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Therapeutic Ultrasonography 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