Hybrid materials composed of superparamagnetic iron oxide nanoparticles (SPIONs) and lipid self-assemblies possess considerable applicative potential in the biomedical field, specifically, for drug/nutrient delivery. Recently, we showed that SPIONs-doped lipid cubic liquid crystals undergo a cubic-to-hexagonal phase transition under the action of temperature or of an alternating magnetic field (AMF). This transition triggers the release of drugs embedded in the lipid scaffold or in the water channels. In this contribution, we address this phenomenon in depth, to fully elucidate the structural details and optimize the design of hybrid multifunctional carriers for drug delivery. Combining small-angle X-ray scattering (SAXS) with a magnetic characterization, we find that, in bulk lipid cubic phases, the cubic-to-hexagonal transition determines the magnetic response of SPIONs. We then extend the investigation from bulk liquid-crystalline phases to colloidal dispersions, i.e., to lipid/SPIONs nanoparticles with cubic internal structure (“magnetocubosomes”). Through Synchrotron SAXS, we monitor the structural response of magnetocubosomes while exposed to an AMF: the magnetic energy, converted into heat by SPIONs, activates the cubic-to-hexagonal transition, and can thus be used as a remote stimulus to spike drug release “on-demand”. In addition, we show that the AMF-induced phase transition in magnetocubosomes steers the realignment of SPIONs into linear string assemblies and connect this effect with the change in their magnetic properties, observed at the bulk level. Finally, we assess the internalization ability and cytotoxicity of magnetocubosomes in vitro on HT29 adenocarcinoma cancer cells, in order to test the applicability of these smart carriers in drug delivery applications.

Magnetoplasmonic NPs have shown remarkable potential in hyperthermia, Magnetic Resonance Imaging (MRI), and Surface Enhanced Raman Scattering (SERS) imaging and diagnostics. However, despite their potential, effective clinical translation remains extremely limited due to a lack of fundamental knowledge about the biological response to these materials, and ongoing efforts seek to bridge the gap between nanomaterial production and effective application. To overcome these hurdles, the combination of inorganic NPs with lipid membranes has emerged as a promising strategy for the biocompatibilization of nanomaterials, preserving the inherent properties of each component and exhibiting novel synergistic functionalities. In this study, we synthesize magnetic-plasmonic-liposome adducts via spontaneous self-assembly. The interaction between magnetic-plasmonic NPs and liposomes was addressed from a physicochemical point of view as a function of liposome composition and concentration. By combining Cryogenic Microscopy, UV-visible spectroscopy and Dynamic Light Scattering we demonstrated that the rigidity of the lipid membrane affects the aggregation of the NPs and the colloidal stability of the NPs-vesicle hybrids. The magnetic responsivity of the hybrids is enhanced as a consequence of the colocalization and crowding of NPs on the lipid membranes and can be finely modulated by varying the number of particles per vesicle. Overall, these results pave the way for the development of multifunctional materials with controlled magnetic-plasmonic properties for a variety of technological applications.