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

Ferroptosis,as a type of programmed cell death process, enableseffective damage to various cancer cells. However, we discovered thatpersistent oxidative stress during ferroptosis can upregulate theapurinic/apyrimidinic endonuclease 1 (APE1) protein that induces therapeuticresistance (ferroptosis resistance), resulting inan unsatisfactory treatment outcome. To address APE1-induced therapeuticresistance, we developed a GSH/APE1 cascade activated therapeuticnanoplatform (GAN). Specifically, the GAN is self-assembled by DNA-functionalizedultrasmall iron oxide nanoparticles and further loaded with drug molecules(drug-GAN). GSH-triggered GAN disassembly can turn onthe 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 releasefor overcoming ferroptosis resistance and inducing the recovery ofnear-infrared fluorescence for imaging the dynamics of APE1. Importantly,adaptive drug release can overcome the adverse effects of APE1 upregulationby boosting intracellular ROS yield and increasing DNA damage, tooffset APE1's functions of antioxidant and DNA repair, thusleading to adaptive ferroptosis. Moreover, with overexpressed GSHand upregulated APE1 in the tumor as stimuli, the therapeutic specificityof ferroptosis toward the tumor is greatly improved, which minimizednonspecific activation of catalysis and excessive drug release innormal tissues. Furthermore, a switchable MRI contrast from negativeto positive is in sync with ferroptosis activation, which is beneficialfor monitoring the ferroptosis process. Therefore, this adapted imagingand therapeutic nanoplatform can not only deliver GSH/APE1-activatedlipid peroxide mediated adaptive synergistic therapy but also provideda switchable MRI/dual-channel fluorescence signal for monitoring ferroptosisactivation, drug release, and therapy resistance dynamics in vivo,leading to high-specificity and high-efficiency adaptive ferroptosistherapy.

Automated summary

This study discovered that persistent oxidative stress during ferroptosis can upregulate the APE1 protein, leading to therapeutic resistance. To address this issue, researchers developed a GSH/APE1 cascade activated therapeutic nanoplatform (GAN) that can induce efficient lipid peroxidation for ferroptosis therapy.