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

Abstract 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). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)‐guided high‐performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex 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) (remodeling TME). This accumulated H + and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex 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 nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1‐mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI‐guided high‐performance ferroptosis therapy of tumors.