Mn(II)-Aloe-Emodin Nanoscale Coordination Polymer Enhances Ferroptosis by Synergistically Enhancing Reactive Oxygen Species Generation via the Nrf2-GPX4 Axis.

Ferroptosis induction is particularly promising for cancer therapy when the apoptosis pathway is compromised. Current strategies in nanomedicine for inducing ferroptosis primarily focus on promoting the accumulation of reactive oxygen species (ROS). However, the presence of intracellular antioxidants, such as nuclear factor erythroid 2-related factor 2 (Nrf2), can limit the effectiveness of such therapy by activating detoxification systems and eliminating ROS. To overcome this challenge, a simple one-step strategy for the construction of Mn 2+ -aloe-emodin (AE) nanoscale coordination polymers (MAP NPs) with ultrahigh loading capacity, followed by the modification of polyvinyl pyrrolidone (PVP), was developed. In the tumour microenvironment (TME), these NPs degraded and released AE and Mn(II), facilitating the generation of ROS and Mn(IV) through a Fenton-like reaction between H 2 O 2 and Mn(II). Mn(IV) subsequently interacted with glutathione (GSH) to induce a cyclic catalytic effect, and the depletion of GSH diminished the activation of glutathione-dependent peroxidase 4 (GPX4). Furthermore, AE inhibited the activity of Nrf2 and depleted GSH, thereby synergistically enhancing antitumour efficacy. Our study demonstrated that MAP NPs effectively generate a robust ROS storm within tumour cells, suggesting that high-performance ferroptosis therapy is effective. Additionally, the inclusion of Mn(II) in the MAP NPs enabled real-time monitoring of therapeutic efficacy via magnetic resonance T1-weighted contrast imaging. This article is protected by copyright. All rights reserved.