A Strategy of Fenton Reaction Cycloacceleration for High Performance Ferroptosis Therapy Initiated by Tumor Microenvironment Remodeling.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H 2 O 2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). In this study, w e propose a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high performance ferroptosis therapy of tumors. The synthesized nanocomplex (named as CON3-LAP-HMON@GF7-ABS-PEG) exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (i.e., remodeling TME). This accumulated H + and abundant glutathione (GSH) in TME synergistically trigger biodegradation of CON3-LAP-HMON@GF7-ABS-PEG to release the loaded cuprous oxide nanodots (CON), β-lapachon (LAP), Fe 3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and NADPH quinone oxidoreductase1 (NQO1)-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides (LPO) accumulation for high performance ferroptosis of tumor cells. The GF network detached from HMON has a improvement of relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME via o ur CON3-LAP-HMON@GF7-ABS-PEG is promising for MRI-guided high performance ferroptosis therapy of tumors . This article is protected by copyright. All rights reserved.