An electrophilicity-engineered magnetic sensor for MRI detection of dormant tumor cell clusters

In magnetic resonance imaging (MRI), direct dipole-dipole interactions between paramagnetic metal centers and water molecules govern the T₁ relaxation of contrast agents. Metal chelates featuring multiple unpaired electrons have long dominated MRI contrast agents. Despite theoretically offering more paramagnetic centers per probe, nanoparticle-based contrast agents have struggled because of the insufficient direct dipolar interactions with water, impeding their clinical adoption. Here, we present an electrophilicity-engineered magnetic sensor (EEMS), which leverages high-electronegativity metal atoms to enhance the electrophilicity of paramagnetic centers in nanosensors, enabling direct electrophilic catalytic dipolar interactions (ECD) with water for enhanced MRI. EEMS demonstrates robust T₁ contrast with a longitudinal relaxivity of 23.2 per millimolar per second at 9 tesla, visualizing tumor cell clusters as small as 68.5 micrometer in vivo. ECD-MRI allows detecting and precise resection of axillary lymph nodes containing dormant tumor cell clusters, achieving 100% survival in mice 100 days postsurgery. EEMS-enhanced ECD-MRI presents a transformative imaging principle for noninvasive visualization of previously undetectable biological entities.