Herein, we use two exemplary superparamagnetic iron oxide
multicore
nanoparticles (SPIONs) to illustrate the significant influence of
slightly different physicochemical properties on the cellular and
molecular processes that define SPION interplay with primary neural
cells. Particularly, we have designed two different SPION structures,
NFA (i.e., a denser multicore structure accompanied by a slightly
less negative surface charge and a higher magnetic response) and NFD
(i.e., a larger surface area and more negatively charged), and identified
specific biological responses dependent on SPION type, concentration,
exposure time, and magnetic actuation. Interestingly, NFA SPIONs display
a higher cell uptake, likely driven by their less negative surface
and smaller protein corona, more significantly impacting cell viability
and complexity. The tight contact of both SPIONs with neural cell
membranes results in the significant augmentation of phosphatidylcholine,
phosphatidylserine, and sphingomyelin and the reduction of free fatty
acids and triacylglycerides for both SPIONs. Nonetheless, NFD induces
greater effects on lipids, especially under magnetic actuation, likely
indicating a preferential membranal location and/or a tighter interaction
with membrane lipids than NFA, in agreement with their lower cell
uptake. From a functional perspective, these lipid changes correlate
with an increase in plasma membrane fluidity, again larger for more
negatively charged nanoparticles (NFD). Finally, the mRNA expression
of iron-related genes such as Ireb-2 and Fth-1 remains unaltered, while TfR-1 is
only detected in SPION-treated cells. Taken together, these results
demonstrate the substantial impact that minor physicochemical differences
of nanomaterials may exert in the specific targeting of cellular and
molecular processes. A denser multicore structure generated by autoclave-based
production is accompanied by a slight difference in surface charge
and magnetic properties that become decisive for the biological impact
of these SPIONs. Their capacity to markedly modify the lipidic cell
content makes them attractive as lipid-targetable nanomedicines.