Tumor Microenvironment–Activated Nanostructure to Enhance MRI Capability and Nanozyme Activity for Highly Tumor‐Specific Multimodal Theranostics

Abstract Copper‐based nanozymes exhibit excellent antitumor activity but are easily inactivated due to the disturbance of proteins or other macromolecules with sulfhydryl. A tumor microenvironment‐responsive CuMnO@Fe₃O₄ (CMF) core–shell nanozyme for highly efficient tumor theranostics is developed. A platelet‐derived growth factor receptor‐β‐recognizing cyclic peptide (PDGFB) target is conjugated to the surface of CMF to fabricate a tumor‐specific nanozyme (PCMF). The core–shell nanostructure significantly avoids the oxidation and inactivation of copper‐based nanozyme, promoting the antitumor activity of PCMF. The weak acid‐ and GSH‐activated T₁ and T₂ relaxation rate of PCMF contributes to T₁ and T₂ dual contrast imaging at the tumor site. In addition, the PCMF disintegrates and produces some metal ions that possess Fenton catalytic activity (i.e., Cu⁺, Mn²⁺, and Fe²⁺) under TME. This process significantly depletes GSH, accelerates Fenton and Fenton‐like reactions, enhances cellular reactive oxygen species (ROS) levels, and induces cancer cell apoptosis and ferroptosis. PCMF also exhibits photothermal functions, so it can be used in combined photothermal therapy, ferroptosis therapy, and chemodynamic therapy, improving anticancer activity. This work provides insights into the design of an exquisite nanostructure for high‐sensitive and tumor‐specific theranostics.