Protease‐Activatable Nanozyme with Photoacoustic and Tumor‐Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy

Abstract Despite the promise of ferrotherapy in cancer treatment, current ferrous therapeutics suffer from compromised antitumor ferroptosis efficacy and low specificity for tumors. Herein, a protease‐activatable nanozyme (Fe 3 O 4 @Cu 1.77 Se) is reported for photoacoustic and tumor‐enhanced magnetic resonance imaging (MRI)‐guided second near‐IR photothermal ferroptosis cancer therapy. Fe 3 O 4 @Cu 1.77 Se remains stable in physiological conditions, but disintegrates to increase reactive intratumoral ferrous supply for elevated hydroxyl radical generation by Fenton reaction and GSH depletion in response to overexpressed matrix metalloproteinases in tumor microenvironment, leading to amplified ferroptosis of tumor cells as well as enhanced T 2 ‐weighted MRI contrast. Further integration with second near‐IR photoirradiation to generate localized heat not only triggers effective photothermal therapy and photoacoustic imaging but more importantly, potentiates Fenton reaction to promote ferroptotic tumor cell death. Such synergism leads to the polarization of tumor‐associated macrophage from the tumor‐promoting M2 type to the tumor‐killing M1 type, and induces the immunogenic cells death of tumor cells, which in turn promotes the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumor, contributing to significant tumor suppression. This study presents a novel activatable ferrous nanotheranostics for spatial‐temporal control over antitumor ferroptosis responses.