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

## TL;DR

Researchers developed iron oxide nanoparticles with tailored surface chemistries to enhance MRI contrast at ultra-high magnetic fields.

## Contribution

A ligand-driven strategy was introduced to optimize T2 relaxivity in iron oxide nanoparticles for ultra-high-field MRI.

## Key findings

- CA-coated nanoparticles achieved record T2 relaxivity values at 3T and 9.4T.
- Ligand chemistry, not shell thickness, primarily influences relaxivity and MRI performance.
- Phantom results accurately predicted in vivo performance in rat brain models.

## Abstract

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 (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 r
2. CA‐coated T
2 contrast agents exhibited record‐high r
2 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 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.

Ligand‐tailored iron oxide nanoparticles reveal how surface chemistry controls T2 relaxivity and in vivo performance in ultra‐high‐field MRI. Systematic variation of hydrophilicity and charge across five coatings modulated r
2 by up to 333 mm
−
1 s−
1, with chemical properties, rather than shell thickness, dictating magnetic dephasing and enabling reliable translation from phantom studies to rat brain in vivo models.