GSH/Ph Dual Activatable Crosslinked And Fluorinated Pei for Cancer Gene Therapy Through Endogenous Iron De-Hijacking And in Situ Ros Amplification.

Ferroptosis-related cancer therapy is limited by insufficient Fe 2+ /Fe 3+ redox pair and hydrogen peroxide (H 2 O 2 ) for producing lethal hydroxyl radicals (•OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine was developed for responsive LIP release and H 2 O 2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated anti-tumor effects. A GSH/pH dual activatable fluorinated and crosslinked polyethyleneimine with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX) plasmids (FP@MC) were developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids were constructed to knock down carbonic anhydrase IX and translate KillerRed-SuperOxide Dismutase recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidified the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generated H 2 O 2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravated cancer ferroptosis and suppressed tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy. This article is protected by copyright. All rights reserved.