A Tumor‐Targeted tRF Therapeutics Triggers Ovarian Cancer Ferroptosis via Dual Inhibition of System Xc ⁻

The severe chemoresistance-caused high recurrence has made ovarian cancer (OVCA) the most lethal gynecological malignancy in clinical practice. Ferroptosis represents a promising therapeutic approach for OVCA, which could effectively overcome tumor resistance. Nevertheless, the traditional ferroptosis inducers lack specificity and selectivity, resulting in poor therapeutic effects. Here, we identified a novel tRNA-derived fragment, tRF-21-XSXMSL73E (tRF-21), which could serve as a ferroptosis inducer to efficiently suppress OVCA growth through dual inhibition of the system Xc^-/glutathione (GSH)/peroxidase 4 (GPX4) axis without causing obvious side effects. Mechanistically, tRF-21 promotes SLC3A2 ubiquitination via SPOP E3 ligase and destabilizes SLC7A11 mRNA by disrupting NSUN2-mediated m⁵C methylation. This dual-inhibition effect on the system Xc^-/GSH/GPX4 axis leads to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death. To enhance therapeutic delivery, we engineered a pH-responsive nanoplatform (tRF-21@EPH) with an ellagic acid core, polyetherimide (PEI) intermediate layer, and hyaluronic acid shell, enabling nuclease protection and tumor-specific uptake. This system markedly improved tRF-21 efficacy with minimal toxicity, providing a novel RNA-based strategy for OVCA treatment.