Abstract 557: A novel tumor targeted extracellular vesicle based iron nanoparticle delivery system to induce ferroptosis and overcome chemoresistance in lung cancer

Abstract Introduction: Cisplatin (CDDP) and its analogs are widely used in lung cancer (LC) treatment. However, despite their effectiveness, advanced LC has a poor 5-year survival rate of less than 10% due to chemoresistance. This resistance is often driven by disrupting apoptosis, a key hallmark of cancer. Ferroptosis, an iron-dependent, non-apoptotic cell death pathway driven by lipid peroxidation, presents a promising alternative to bypass apoptotic resistance. In this study, we developed a novel, tumor-specific delivery system, ExoFeRTF, based on extracellular vesicles (EVs) functionalized with transferrin (TF) and loaded with iron oxide nanoparticles (IONPs). This system is designed to target transferrin receptors on LC cells to induce ferroptosis, thereby overcoming chemoresistance in a targeted manner. Methods: ExoFeRTF was synthesized by loading IONPs into TF-decorated EVs derived from MRC-9 lung fibroblast cells. The structural and functional integrity of ExoFeRTF was confirmed through physicochemical characterization. To assess its therapeutic efficacy in reversing chemoresistance, ExoFeRTF was tested on CDDP-resistant LC cells, patient-derived tumoroids (PDTs), and circulating tumor cell (CTC)derived xenograft (cDXT) cells and xenograft mouse models. We evaluated cell viability, mitochondrial damage, glutathione (GSH) levels, and expression changes in key ferroptosis markers (xCT/SLC7A11, GPX4). Molecular mechanisms of ferroptosis induction were also explored. In vivo, ExoFeRTF tumor targeting was confirmed in LC xenograft models using Magnetic Resonance Imaging and Prussian Blue staining. Results: ExoFeRTF demonstrated robust structural stability, targeted tumor localization, and effective induction of ferroptosis in CDDP-resistant LC cells, PDTs, cDXT cells and xerograph mouse models. Treatment with ExoFeRTF led to mitochondrial disruption, GSH depletion, and downregulation of ferroptosis markers. Additionally, Nrf2, a key regulator of antioxidant responses and chemoresistance, was downregulated with reduced intracellular translocation in ExoFeRTF-treated cells. Subsequent CDDP treatment further sensitized the cells, indicating a reversal of chemoresistance. Conclusion: ExoFeRTF offers a promising, tumor-targeted approach to overcoming chemoresistance in lung cancer by inducing ferroptosis, a non-apoptotic cell death mechanism. These findings support the potential of ExoFeRTF as a novel therapeutic strategy for treating resistant lung cancer, providing a foundation for future clinical applications in combatting chemoresistant cancers. Citation Format: Anjugam Paramanantham, Rahmat Asfiya N/A, Akhil Srivastava. A novel tumor targeted extracellular vesicle based iron nanoparticle delivery system to induce ferroptosis and overcome chemoresistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 557.