GSH/APE1 Cascade-Activated Nanoplatform for Imaging Therapy Resistance Dynamics and Enzyme-Mediated Adaptive Ferroptosis.

Ferroptosis, as a type of programmed cell death process, enables effective damage to various cancer cells. However, we discovered that persistent oxidative stress during ferroptosis can upregulate the apurinic/apyrimidinic endonuclease 1 (APE1) protein that induces therapeutic resistance ("ferroptosis resistance"), resulting in an unsatisfactory treatment outcome. To address APE1-induced therapeutic resistance, we developed a GSH/APE1 cascade activated therapeutic nanoplatform (GAN). Specifically, the GAN is self-assembled by DNA-functionalized ultrasmall iron oxide nanoparticles and further loaded with drug molecules (drug-GAN). GSH-triggered GAN disassembly can "turn on" the catalysis of GAN to induce efficient lipid peroxidation (LPO) for ferroptosis toward the tumor, which could upregulate APE1 expression. Subsequently, upregulated APE1 can further trigger accurate drug release for overcoming ferroptosis resistance and inducing the recovery of near-infrared fluorescence for imaging the dynamics of APE1. Importantly, adaptive drug release can overcome the adverse effects of APE1 upregulation by boosting intracellular ROS yield and increasing DNA damage, to offset APE1's functions of antioxidant and DNA repair, thus leading to adaptive ferroptosis. Moreover, with overexpressed GSH and upregulated APE1 in the tumor as stimuli, the therapeutic specificity of ferroptosis toward the tumor is greatly improved, which minimized nonspecific activation of catalysis and excessive drug release in normal tissues. Furthermore, a switchable MRI contrast from negative to positive is in sync with ferroptosis activation, which is beneficial for monitoring the ferroptosis process. Therefore, this adapted imaging and therapeutic nanoplatform can not only deliver GSH/APE1-activated lipid peroxide mediated adaptive synergistic therapy but also provided a switchable MRI/dual-channel fluorescence signal for monitoring ferroptosis activation, drug release, and therapy resistance dynamics in vivo, leading to high-specificity and high-efficiency adaptive ferroptosis therapy.