NIR-II Type I AIE Photosensitiser-Functionalized MOF-Cu Nanoplatform Promotes Ferroptosis and Cuproptosis for Antitumor Therapy.

Abstract

Cancer therapeutic strategies centered on synergistic ferroptosis and cuproptosis have attracted considerable interest. However, current approaches predominantly relying on Fe and Cu sources face limitations including single mode of reactive oxygen species (ROS) production, poor organelle targeting, and lack of imaging capabilities. Herein, we developed a multifunctional nanoplatform, NMC NPs, by integrating a type I aggregation-induced emission photosensitizer (NTI) with a Cu-based nanozyme (MOF-Cu). This design enables efficient ROS generation, precise mitochondria targeting, and real-time fluorescence imaging, allowing more effective activation of ferroptosis and cuproptosis. Upon cellular uptake, MOF-Cu framework dissociates and releases NTI, which selectively accumulates in mitochondria. Under 635 nm laser irradiation, NTI generates type I ROS, triggering lipid peroxidation and activating ferroptosis. Simultaneously, MOF-Cu nanozyme exerts dual peroxidase-like and glutathione peroxidase-like activities, catalyzing H2O2 into hydroxyl radicals while depleting glutathione and releasing Cu+ ions, further promoting ferroptosis. Notably, the released Cu+ ions further disrupt mitochondrial function, induce dihydrolipoamide S-acetyltransferase aggregation, and activate cuproptosis. The synergistic action efficiently enhances immunogenic cell death. In vivo studies confirmed the potent antitumor efficacy of NMC NPs with minimal side effect. This study provides new insights into the cooperative regulation of metal-dependent cell death and advances the design of integrated theranostic nanoplatforms.