2682 - Programmable Polynucleotide-Iron Nanoscaffolds Potentiate Radiotherapy in TNBC via Ferroptosis-Driven Immunomodulation
Presenter(s)
P. Zou1,2, X. Gao3, J. Lang1,2, and M. Chen1,2; 1Department of Radiation Oncology, Precision Radiation in Oncology Key Laboratory of Sichuan Province, Chengdu, Sichuan, China, 2Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China, 3State Key Laboratory Base of Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong, China
Purpose/Objective(s): Radio-resistance in triple-negative breast cancer (TNBC) stems from aggressive DNA repair and metabolic plasticity. To breach these barriers, we propose a supramolecular strategy elevating Ara-AMP from a metabolic drug to a structural building block. We engineered a “strong coordination/weak locking” dual-network (AFA-NPs), where Ara-AMP coordinates Fe(III) via multidentate sites, stabilized by a secondary 3-aminobenzamide (3-AB) network. We hypothesized this architecture remains inert physiologically but undergoes programmed disassembly within the acidic, reductive tumor microenvironment (TME). This collapse releases a cascade disrupting redox homeostasis and inhibiting DNA repair, sensitizing TNBC to radiotherapy (RT) and converting tumors into in situ vaccines.
Materials/Methods: AFA-NPs were synthesized via molecular dynamics-guided coordination. The skeleton utilized Ara-AMP to chelate Fe(III), while 3-AB provided a secondary “soft lock” via hydrophobic stacking. Stability and stimuli-responsive degradation were profiled. Radiosensitization was evaluated in 4T1 and MDA-MB-231 cells via clonogenic assays and flow cytometry. Orthotopic TNBC models received AFA-NPs plus X-ray (6 Gy) to assess tumor regression and immune remodeling.
Results: AFA-NPs formed uniform spherical structures (136 ± 4.3 nm) with high physiological stability but rapid disassembly (t1/2 < 2 h) upon TME stimulation. This dismantling released payloads to synergize with RT. In vitro, combination therapy reduced survival at 4 Gy (SF4) to 0.18 vs. 0.55 (RT-only), yielding a sensitization enhancement ratio (SER) of 1.72. Intracellular release of iron/Ara-AMP overwhelmed antioxidant defenses, triggering a 4.5-fold increase in lipid ROS and GSH depletion, indicating robust ferroptosis. In vivo, AFA-NPs + RT achieved 78.8% tumor growth inhibition (TGI), significantly outperforming RT alone (26.6%). Notably, ferroptotic stress elevated intratumoral CD8+ T cells to 28.5% (vs. 6.2% in controls), confirming a transition to a “hot” phenotype.
Conclusion: This validates a “material-mechanism” strategy where Ara-AMP and 3-AB serve dual roles as scaffolds and stressors. By orchestrating a nuclear-to-membrane strike, AFA-NPs convert RT damage into lethal ferroptosis and immune activation. This offers a promising paradigm to overcome radioresistance in refractory TNBC.