García Acevedo, PelayoAlonso Alonso, María LuzOrtega Espina, SaraBañobre López, ManuelPiñeiro Redondo, YolandaIglesias Rey, RamónRivas Rey, José2026-04-212026-04-212026-02-03García‐Acevedo, P., Alonso‐Alonso, M. L., Ortega‐Espina, S., Bañobre‐López, M., Piñeiro, Y., Iglesias‐Rey, R., & Rivas, J. (2026). Ligand‐driven optimization of iron oxide nanoprobes for in vivo MRI enhancement at ultra‐high field. Small Journal, 22. https://doi.org/10.1002/smll.2025097921613-6810https://hdl.handle.net/10347/46870Ultra-high-field magnetic resonance imaging (UHF-MRI, B0 > 7 T) combined with contrast enhancement (CE-MRI) offersunmatched 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 thermaldecomposition. Five surface chemistries–polyacrylic acid (PAA), poly(isobutylene-alt-maleic anhydride) (PMA), poly(maleicanhydride-alt-1-octadecene) (PMAO), citric acid (CA), and silica (SiO2 )─ were investigated under physiological conditions andin 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 T2contrast 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 withinthe superparamagnetic size range (d < 20 nm). Correlations of r2 with hydrodynamic size, ζ-potential, and coating thicknessrevealed that ligand chemistry–specifically hydrophilicity and anionic surface charge–dominates over physical shell dimensionsin 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.eng© 2026 International Iberian Nanotechnology Laboratory and The Author(s). Small published by Wiley-VCH GmbH This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.http://creativecommons.org/licenses/by/4.0/Contrast agentsLigand exchangeMagnetic contrast agentsMagnetic resonanceUltra high field-MRIjournal article10.1002/smll.2025097921613-6829open access