Self-amplifying nanomedicine reprograms redox metabolism to trigger immunogenic ferroptosis in colon cancer: multiomics identifies AMPD3 as a novel regulator

Ferroptosis represents a promising antitumor strategy, yet its efficacy in colon Cancer is compromised by excessive antioxidant glutathione (GSH) and insufficient Reactive Oxygen Species (ROS). To address this limitation, we rationally designed integrated nanoplatforms (FeBMnDC NPs) by covalently conjugating albumin-MnO₂ complexes with ferritin to codeliver the ROS-responsive dihydroartemisinin (DHA) dimer and Photosensitizer Chlorin e6 (Ce6). This design synergistically disrupts redox homeostasis to induce Ferroptosis and immune activation. Upon tumor accumulation and laser irradiation, the FeBMnDC NPs release oxygen, Mn²⁺, ferritin, DHA, and Ce6. Laser-triggered ROS initiates a self-amplifying feedback loop that further releases DHA and Ce6, enhancing ROS generation via chemodynamic and photodynamic therapies, while MnO₂ degradation and ferric ion reduction deplete GSH. Severe oxidative stress promotes Apoptosis, Ferroptosis, and immunogenic cell death. In vitro and in vivo studies confirmed that FeBMnDC NPs enhance lipid peroxidation and dendritic cell maturation, achieving potent antitumor efficacy without apparent side effects. Moreover, integrated transcriptomic and proteomic analyses revealed that laser irradiation reprograms GSH metabolism and activates ferroptosis-executing pathways, identifying AMPD3 as a novel ferroptosis-associated gene in colon Cancer. This work presents a self-amplifying nanoplatform enabling multimodal redox intervention, offering a mechanism-driven strategy for colon Cancer treatment.