Self‐Assembled Tetrahedral Framework Nucleic Acids Alleviate Pulmonary Hypertension by Regulating Calcium Homeostasis

Abstract Pulmonary hypertension (PH) is a life‐threatening cardiovascular disease characterized by cellular hyperproliferation and vascular remodeling, leading to heart failure. 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‐small 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‐functional analysis reveals that tFNAs significantly improve pulmonary artery acceleration time, reduce vascular wall thickness, and decrease α‐SMA and PCNA expression. Cardiac structural‐functional 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‐Akt pathway, thus ameliorating PA and RV remodeling. This study presents a novel DNA nanomaterial‐based strategy for PH treatment and establishes a mechanistic foundation for future clinical applications.