Tumor Microenvironment-Responsive Lipid PeroxidationAmplifier: Harnessing Ferroptosis Resistance to Devastate the FerroptosisDefense System

Amplification of lipid peroxidation with tumor specificity represents a new avenue to boost ferroptosis-mediated anticancer therapeutics but remains challenging. Herein, we proposed a metal-phenolic-network (MPN)-coated nanohybrid as a tumor microenvironment-responsive lipid peroxidation amplifier, consisting of reactive oxygen species generator MPN, glutathione (GSH) scavenger GSH-P, and glutathione peroxidase 4 (GPX4) mRNA gene silencing sequence. The protective MPN shell of this amplifier can be specifically disintegrated by acidic and adenosine triphosphate (ATP)-rich tumor microenvironments to induce oxidative stress through the dual disruption of redox homeostasis (Fenton-catalytic reactive oxygen species accumulation and GSH depletion). Furthermore, the oxidative stress-induced upregulation of ferroptosis resistance-related apurinic/apyrimidinic endonuclease 1 (APE1) is further ingeniously employed as an amplification element to prompt the release of apurinic/apyrimidinic (AP) site-embedded GPX4 mRNA gene silencing sequence which can downregulate the GPX4 level. Based on tandem depletion of the GSH substrate and gene silencing of GPX4, the ferroptosis defense system of GPX4/GSH can be heavily devastated to enable amplification of lipid peroxidation for effectively and specifically improving ferroptosis efficiency. We expect this strategy can be further expanded to other important regulatory proteins and provide a mechanism study for ferroptosis-mediated therapy.