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

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Nanomedicine

Background:

• Pulmonary hypertension (PH) is a severe cardiovascular disease with limited treatment options.
• PH involves pathological vascular remodeling and cellular hyperproliferation, often leading to heart failure.
• Existing therapies for PH lack efficacy and safety, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the therapeutic potential of tetrahedral framework nucleic acids (tFNAs) for treating pulmonary hypertension (PH).
• To explore the mechanism of tFNAs in regulating calcium homeostasis and ameliorating PH-associated vascular and cardiac remodeling.
• To establish a foundation for the clinical application of DNA nanomaterials in PH treatment.

Main Methods:

• Synthesis and characterization of ultra-small, stable, and biocompatible tFNAs.
• In vitro assessment of tFNA cellular uptake, proliferation, and migration in pulmonary artery smooth muscle cells.
• In vivo evaluation of tFNA efficacy in a PH animal model, including pulmonary artery and cardiac structural-functional analysis.
• Transcriptomic and biochemical analyses to elucidate the molecular mechanisms of tFNA action.

Main Results:

• tFNAs demonstrated enhanced cellular uptake and suppressed proliferation/migration of pulmonary artery smooth muscle cells.
• In vivo studies showed tFNAs improved pulmonary artery acceleration time, reduced vascular wall thickness, and decreased key markers of proliferation and smooth muscle differentiation (α-SMA, PCNA).
• tFNAs enhanced exercise capacity, reduced cardiac fibrosis, and improved the Fulton index, indicating alleviation of right ventricular (RV) remodeling. Mechanistically, tFNAs upregulated SERCA2a, downregulated VEGFD, restored calcium homeostasis, and modulated the PI3K-Akt pathway.

Conclusions:

• This study presents a novel DNA nanomaterial-based therapeutic strategy for pulmonary hypertension (PH) utilizing tFNAs.
• tFNAs effectively ameliorate PH by restoring calcium homeostasis and modulating key signaling pathways involved in vascular and cardiac remodeling.
• The findings provide a strong mechanistic basis for the future clinical translation of tFNAs in treating PH.