Ligand biodegradation-induced surface reconstruction of magnetite nanoparticles: potentially overlooked toxicity

Abstract

The coating of nanoparticles (NPs) with biodegradable ligands has been considered an efficient way to improve the biocompatibility of NPs and to decrease their biopersistence. However, the role of ligand biodegradation in reshaping the core material and the resulting change in toxicity have not been fully explored. In this study, magnetite (Fe₃O₄) NPs coated with a high or low loading of hyaluronic acid (termed Fe₃O₄–HA_H and Fe₃O₄–HA_L) were synthesized. Fe₃O₄–HA_R was obtained after the enzymatic degradation of Fe₃O₄–HA_H by a hyaluronidase, which had a coating weight similar to that of Fe₃O₄–HA_L, as verified by thermogravimetric analysis. Interestingly, among the three NPs, Fe₃O₄–HA_R induced the highest rate of cellular damage. In particular, 2 times more hydroxyl radicals were detected in cells stressed by Fe₃O₄–HA_R than in cells stressed by Fe₃O₄–HA_H, despite the highest cellular uptake being observed for Fe₃O₄–HA_H because of the ligand–receptor interactions between hyaluronic acid and membrane receptors. The structural characterization results revealed that ligand degradation induced notable surface reconstruction of the Fe₃O₄ core, showing a characteristic Fe₃O₄@Fe₂O₃ structure with surface-bound ferrous ions. This unique structure endowed Fe₃O₄–HA_R with superior competency in initiating the Fenton reaction and accelerating the Fe(III)/Fe(II) cycle. Our results emphasize the importance of tracing the in vivo biotransformation of NPs from all of the different architectural parts, particularly deciphering the interplay among the core, shell, surface ligands, and surrounding ions.