Metal‐Ion‐Activity Magnetic Nanoprobes for MRI Sensing of Cu ²⁺ Levels in Tumor Malignancy

Abstract Metal ions are essential for enzymatic regulation, redox balance, and signal transduction, with dysregulation increasingly implicated in cancer, neurodegeneration, and inflammation. Copper ions (Cu ²⁺ ), in particular, are closely associated with tumor progression and malignancy. However, conventional binding‐based magnetic resonance imaging (MRI) probes lack the sensitivity to detect trace metal ion fluctuations in vivo. Here, a metal‐ion‐activity magnetic (MIAM) nanoprobe is reported that integrates activity‐based chemical sensing with magnetic resonance energy transfer for signal amplification. MIAM nanoprobe consists of superparamagnetic iron oxide nanoparticles (SPIONs) linked to gadoteric acid (Gd‐DOTA) via a Cu ²⁺ ‐cleavable adipic acid dihydrazide moiety. The T ₁ ‐MRI signal is initially quenched as SPIONs suppress Gd‐DOTA's relaxivity. Upon exposure to elevated Cu ²⁺ , Cu ²⁺ ‐catalyzed reaction breaks the covalent bond in the MIAM nanoprobe and then releases free Gd‐DOTA, resulting in an activated T ₁ ‐MRI signal. The catalytic nature of this reaction enables multiple turnover events, thereby facilitating signal amplification and enabling sensitive detection of Cu ² ⁺ levels down to ≈10 µ m in vitro, facilitating the identification of tumor malignancy and the evaluation of therapeutic response to Cu ²⁺ chelators. By converting metal ion activity into quantifiable MRI contrast, the MIAM nanoprobe offers a noninvasive platform for diagnosing and tracking various metal‐ion‐associated diseases.