Chemically Neutral, Electrokinetically Charged: Ligand Shell Thickness Governs the Zeta Potential and In Vivo Fate of Ultrasmall HfO2 Nanoparticles
4 affiliations
- 1Department of Chemistry, University of Basel, Mattenstrasse 22, Basel, Switzerland, 4058
- 2Center for Photon Science, Paul Scherrer Institut, Forschungsstrasse 111, Villigen PSI, Switzerland, 5232
- 3Swiss Nanoscience Institute, Klingelbergstrasse 82, Basel, 4056
- 4Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel, Switzerland, 4056
Abstract
Nanoparticles are extensively explored in biological contexts, and while their core composition determines their specific functionality, surface chemistry governs their interactions with the biological environment. In this work, we used ultrasmall (d < 5 nm) hafnium oxide nanoparticles as a model system, given their biocompatibility and established use in contrast-enhanced X-ray computed tomography and external-beam radiotherapy. We systematically compared three surface ligands featuring the same high-affinity nitrocatechol anchoring group but different terminal moieties: a short ethylene glycol (EG) oligomer, a 2 kDa polyethylene glycol (PEG) polymer, and a short zwitterionic (ZW) chain. Despite the neutral character of all ligand tails, only the long PEG chains yielded nanoparticles with a near-neutral zeta potential. The short ligands produced nanoparticles with significantly negative zeta potentials (-30 mV), which was found to be an essential component of their colloidal stability. NPs stabilized with short EG or ZW ligands exhibited enhanced uptake by THP-1 macrophages in vitro and short circulation times in vivo in zebrafish larvae, despite suppressed protein corona formation on ZW nanoparticles. The ZW nanoparticles thus present antifouling but not stealth behavior. In contrast, nanoparticles stabilized with long PEG chains largely escaped detection by the phagocyte system. They exhibited prolonged circulation and extravasation in the zebrafish larva model. Zeta potential showed the strongest correlation with macrophage uptake and biodistribution. It reflects the combined effect of surface charge and steric screening. These results highlight the need for long ligand tails for the design of targeted nanomaterials for therapeutic of imaging applications, which require long circulation times.
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BibTeX
@misc{maksimova2026chemically,
title = {{Chemically Neutral, Electrokinetically Charged: Ligand Shell Thickness Governs the Zeta Potential and In Vivo Fate of Ultrasmall HfO2 Nanoparticles}},
author = {Elizaveta Maksimova and David Wang and Megan Stierli and Nikolina Veljancic and Oya Tagit and Jörg Huwyler and Anne Bonnin and Jonathan De Roo},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15003826/v3},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003826/v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - Chemically Neutral, Electrokinetically Charged: Ligand Shell Thickness Governs the Zeta Potential and In Vivo Fate of Ultrasmall HfO2 Nanoparticles
AU - Elizaveta Maksimova
AU - David Wang
AU - Megan Stierli
AU - Nikolina Veljancic
AU - Oya Tagit
AU - Jörg Huwyler
AU - Anne Bonnin
AU - Jonathan De Roo
PY - 2026
DA - 2026/09/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15003826/v3
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003826/v3
AB - Nanoparticles are extensively explored in biological contexts, and while their core composition determines their specific functionality, surface chemistry governs their interactions with the biological environment. In this work, we used ultrasmall (d < 5 nm) hafnium oxide nanoparticles as a model system, given their biocompatibility and established use in contrast-enhanced X-ray computed tomography and external-beam radiotherapy. We systematically compared three surface ligands featuring the same high-affinity nitrocatechol anchoring group but different terminal moieties: a short ethylene glycol (EG) oligomer, a 2 kDa polyethylene glycol (PEG) polymer, and a short zwitterionic (ZW) chain. Despite the neutral character of all ligand tails, only the long PEG chains yielded nanoparticles with a near-neutral zeta potential. The short ligands produced nanoparticles with significantly negative zeta potentials (-30 mV), which was found to be an essential component of their colloidal stability. NPs stabilized with short EG or ZW ligands exhibited enhanced uptake by THP-1 macrophages in vitro and short circulation times in vivo in zebrafish larvae, despite suppressed protein corona formation on ZW nanoparticles. The ZW nanoparticles thus present antifouling but not stealth behavior. In contrast, nanoparticles stabilized with long PEG chains largely escaped detection by the phagocyte system. They exhibited prolonged circulation and extravasation in the zebrafish larva model. Zeta potential showed the strongest correlation with macrophage uptake and biodistribution. It reflects the combined effect of surface charge and steric screening. These results highlight the need for long ligand tails for the design of targeted nanomaterials for therapeutic of imaging applications, which require long circulation times.
ER -