Chemically Neutral, Electrokinetically Charged: Ligand Shell Thickness Governs the Zeta Potential and In Vivo Fate of Ultrasmall HfO2 Nanoparticles
Year: 2026
Type: preprint
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.
Source: ChemRxiv
Authors: Elizaveta Maksimova, David Wang, Megan Stierli, Nikolina Veljancic, Oya Tagit, Jörg Huwyler, Anne Bonnin, Jonathan De Roo
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7214079063