Composition-tunable polycarboxylic acid-stabilized ultrasmall amorphous paramagnetic nanoclusters as multifunctional MRI contrast agents

Conventional crystalline nanoscale magnetic resonance imaging (MRI) contrast agents (CAs) suffer from low longitudinal relaxivity (r 1) and complex synthesis processes, limiting their clinical translation potential. Here, we report that polycarboxylic acid-stabilized ultrasmall amorphous paramagnetic nanoclusters (UAPNCs), fabricated via a one-step co-precipitation method, are proposed to simultaneously increase the number of inner-sphere coordinated water molecules (q), elevate the second-sphere hydrogen-bonded water molecules (q'), and prolong the rotational correlation time (τ R), thereby achieving consistently excellent r 1 (>20 mM-1s-1; 3.0 T) with a maximum of 41.27 ± 0.33 mM-1s-1 and low r 2/r 1 ratios (<3). Importantly, we propose a mechanism that non-paramagnetic metal doping further boosts r 1 by approximately 40% via elevating q'. In vivo MRI reveals that manganese-based UAPNCs hold dual potential for hepatocyte-specific MRI and contrast-enhanced magnetic resonance angiography (CE-MRA), whereas gadolinium-based UAPNCs excel in CE-MRA. Overall, this work demonstrates the universality and superiority of UAPNCs as CAs, providing a new paradigm for designing next-generation MRI CAs.