AS1411-aptamer-functionalized DNA tetrahedron for targeted delivery of vorinostat to suppress gastric cancer progression via ferroptosis induction and epithelial-mesenchymal transition inhibition.

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.