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 enhance the inner-sphere coordinated water ( q ), second-sphere hydrogen-bonded water ( q '), and the rotational correlation time ( τ R ), thereby achieving consistently excellent r 1 (>20 mM −1 s −1 ; 3.0 T) with a maximum of 41.27 ± 0.33 mM −1 s −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 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.