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

Ultra-high-field magnetic resonance imaging (UHF-MRI, B₀ > 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 T₂ relaxivity (r₂) 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 (SiO₂)─ 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 mm^- ¹ s^- ¹ increase in r₂. CA-coated T₂ contrast agents exhibited record-high r₂ values (522 mm^- ¹ s^- ¹ at 3 T; 381 mm^- ¹ s^- ¹ at 9.4 T) in spherical iron oxide MNPs within the superparamagnetic size range (d < 20 nm). Correlations of r₂ 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 T₂ tuning at UHF, with phantom results reliably predicting in vivo UHF-MRI performance in rat brain models, advancing the design of neuroimaging nanoprobes.