Ligand‐Driven Optimization of Iron Oxide Nanoprobes for In Vivo MRI Enhancement at Ultra‐High Field

Ultra‐high‐field magnetic resonance imaging (UHF‐MRI, B 0 > 7 T) combined with contrast enhancement (CE‐MRI) offers unmatched spatial resolution, but high‐field effects limit the performance of negative contrast agents. Here, we report a ligand‐driven strategy to modulate the T 2 relaxivity ( r 2 ) of monodisperse 12 nm iron oxide‐based contrast agents synthesized by thermal decomposition. Five surface chemistries–polyacrylic acid (PAA), poly(isobutylene‐alt‐maleic anhydride) (PMA), poly(maleic anhydride‐alt‐1‐octadecene) (PMAO), citric acid (CA), and silica (SiO 2 )─ were investigated under physiological conditions and in vivo using relaxometry (1.4 T), clinical (3 T), and UHF (9.4 T) MRI, achieving up to a 333 m m − 1 s − 1 increase in r 2 . CA‐coated T 2 contrast agents exhibited record‐high r 2 values (522 m m − 1 s − 1 at 3 T; 381 m m − 1 s − 1 at 9.4 T) in spherical iron oxide MNPs within the superparamagnetic size range ( d < 20 nm). Correlations of r 2 with hydrodynamic size, ζ‐potential, and coating thickness revealed that ligand chemistry–specifically hydrophilicity and anionic surface charge–dominates over physical shell dimensions in governing water accessibility and magnetic dephasing. This scalable ligand‐exchange strategy enables precise T 2 tuning at UHF, with phantom results reliably predicting in vivo UHF‐MRI performance in rat brain models, advancing the design of neuroimaging nanoprobes.