Metal-Ion-Activity Magnetic Nanoprobes for MRI Sensing of Cu²⁺ Levels in Tumor Malignancy

Metal ions are essential for enzymatic regulation, redox balance, and signal transduction, with dysregulation increasingly implicated in cancer, neurodegeneration, and inflammation. Copper ions (Cu²⁺), 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 Cu²⁺-cleavable adipic acid dihydrazide moiety. The T₁-MRI signal is initially quenched as SPIONs suppress Gd-DOTA's relaxivity. Upon exposure to elevated Cu²⁺, Cu²⁺-catalyzed reaction breaks the covalent bond in the MIAM nanoprobe and then releases free Gd-DOTA, resulting in an activated T₁-MRI signal. The catalytic nature of this reaction enables multiple turnover events, thereby facilitating signal amplification and enabling sensitive detection of Cu²⁺ levels down to ≈10 µm in vitro, facilitating the identification of tumor malignancy and the evaluation of therapeutic response to Cu²⁺ 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.