Abstract

Gastric cancer (GC) exhibits progression and metastatic spread that is tightly linked to ferroptosis and epithelial-mesenchymal transition (EMT). Developing therapies that target both pathways represents a promising clinical strategy. Herein, we identified the histone deacetylase (HDAC) inhibitor vorinostat as a potent dual-pathway modulator through bioinformatics screening. To address its limitations in aqueous solubility and targeting efficiency, a DNA tetrahedron nanostructure conjugated with the AS1411 aptamer (TAV) was synthesized as a novel drug delivery system. The synthesis of TAV was confirmed by PAGE, UV–vis spectroscopy, zeta potential analysis, atomic force microscopy, and drug loading efficiency assessment. In vitro efficacy was evaluated in HGC-27 and MKN-45 cell lines using viability, migration, apoptosis, and ferroptosis assays. Therapeutic effects and biocompatibility were further validated in patient-derived organoids and a nude mouse xenograft model. Vorinostat enhanced p53 protein stability by promoting its acetylation and inhibiting ubiquitination-mediated degradation. The stabilized p53 organized a dual antitumor response by simultaneously promoting ferroptosis via the SLC7A11/GPX4 axis and suppressing EMT through downregulation of N-cadherin, vimentin, and MMP9. Additionally, vorinostat suppressed the PI3K/AKT/mTOR pathway in a p53-independent manner, further contributing to its anti-tumor efficacy. This study demonstrated that the DNA tetrahedron-based nanocarrier functionalized with AS1411 aptamer effectively delivers vorinostat and enhances its dual action on ferroptosis and EMT in GC. This targeted nanoplatform represents a promising strategy for precise and combinatory GC therapy.