Alkali Source Modulates Polydopamine Shell Thickness and Ferroptosis Susceptibility in Iron Oxide Nanoparticles Under...

Controlling nanoparticle surface chemistry through synthesis conditions-rather than postsynthetic modification-represents an attractive strategy for tailoring therapeutic behavior. Here, we report that the choice of alkali source during one-pot co-precipitation of polydopamine-coated iron oxide magnetic nanoparticles (PDA-Fe₃O₄ MNPs) determine their physicochemical identity and downstream biological activity. The type of base influenced particle properties: NaOH (MNP1) produced smaller (9.4 nm), well-crystallized particles with a negative PDA shell (ζ = -25.0 mV), whereas ammonia (MNP2) yielded larger particles (11.2 nm) with a higher positive surface (ζ = +45.5 mV) charge, which was associated with greater cellular uptake. In HUVEC and SH-SY5Y cells, MNPs were biocompatible at low concentrations. In SH-SY5Y cells, when MNP1 was applied with magnetic hyperthermia (MHT+), ROS levels increased to 38.6%, while the lipid peroxidation MFI red/green ratio decreased from ~65 to ~58, indicating a marked ferroptosis tendency. Conversely, MNP2 caused greater membrane damage, with lower ROS production under MHT+ (12.4%) compare to MNP1 (38.6%) and a smaller decline in the lipid peroxidation ratio (from ~60 under MHT- to ~55 under MHT+) in SH-SY5Y. Notably, MNP2's own ROS levels decreased from MHT- (22.8%) to MHT+ (12.4%), the opposite trend observed for MNP1. Ferroptosis-related cell death was not observed in HUVECs, as assessed by ROS and lipid peroxidation assays. Furthermore, the 5.2-fold increase in FTH1 gene expression in SH-SY5Y cells following MNP1 treatment suggests that the cells activate intracellular iron buffering as a bioinorganic defense mechanism and that different cell death pathways associated with ferroptosis may be triggered depending on the type of nanoparticle. Critically, the formulation induced neither significant cytotoxicity nor markers of ferroptosis in HUVECs, suggesting a degree of cancer-cell selectivity for MNPs. These findings establish that base-dependent surface engineering of PDA-Fe₃O₄ MNPs yield functionally distinct nanoplatforms and provide a rational foundation for the design of ferroptosis-enhanced magnetothermal cancer therapies.