Magnetite and maghemite multi-core nanoflowers (NFs) synthesized using the modified polyol-mediated routes are to date among the most effective nano-heaters in magnetic hyperthermia (MHT). Recently, magnetite NFs have also shown high photothermal (PT) performances in the most desired second near infra-red (NIR-II) biological window making them attractive in the field of nanoparticle-activated thermal therapies. However, what makes magnetic NFs efficient heating agents in both modalities still remain an open question. In this work, we investigate the role of many parameters of the polyol synthesis on the final NFs size, shape, chemical composition, number of cores and crystallinity. These nanofeatures are later correlated to the magnetic, optical and electronic properties of the NFs as well as their collective macroscopic thermal properties in MHT and PT to find relationships between their structure, properties and function. We evidence the critical role of iron(III) and heating ramps on the elaboration of well-defined NFs with high number of multi-cores. While MHT efficiency is found to be proportional to the average number of magnetic cores within the assemblies, the optical responses of the NFs and their collective photothermal properties depend directly on the mean volume of the NFs (as supported by optical cross sections numerical simulations) and strongly on the structural disorder in the NFs, rather than the stoichiometry. The concentration of defects in the nanostructures, evaluated by photoluminescence and Urbach energy (EU), evidences a switch in the optical behavior for a limit value of EU = 0.4 eV where a discontinuous transition from high to poor PT efficiency is also observed. Keywordsmulti-core iron oxides, nanoflowers, magnetic nanoparticles, magnetic hyperthermia, photothermia, nanothermal agents, thermal therapies distributions histograms, powder XRD diffraction data and Rietveld refinements, XANES data, 57 Fe Mössbauer spectra, SQUID, TGA, ZFC/FC measurements and DLS measurements, ILP values, Python codes, Beer-Lambert plots at 1064 nm, Urbach and Tauc plots, MHT and PT measurements, fluorescence emission spectra and additional tables.

Despite efforts in producing nanoparticles with tightly controlled designs and specific physicochemical properties, these can undergo massive nano−bio interactions and bioprocessing upon internalization into cells. These transformations can generate adverse biological outcomes and premature loss of functional efficacy. Hence, understanding the intracellular fate of nanoparticles is a necessary prerequisite for their introduction in medicine. Among nanomaterials devoted to theranostics is copper sulfide (CuS), which provides outstanding optical properties along with easy synthesis and low cost. Herein, we performed a long-term multiscale study on the bioprocessing of hollow CuS nanoparticles (CuS NPs) and rattle-like iron oxide nanoflowers@CuS core−shell hybrids (IONF@CuS NPs) when inside stem cells and cancer cells, cultured as spheroids. In the spheroids, both CuS NPs and IONF@ CuS NPs are rapidly dismantled into smaller units (day 0 to 3), and hair-like nanostructures are generated (day 9 to 21). This bioprocessing triggers an adaptation of the cellular metabolism to the internalized metals without impacting cell viability, differentiation, or oxidative stress response. Throughout the remodeling, a loss of IONF-derived magnetism is observed, but, surprisingly, the CuS photothermal potential is preserved, as demonstrated by a full characterization of the photothermal conversion across the bioprocessing process. The maintained photothermal efficiency correlated well with synchrotron X-ray absorption spectroscopy measurements, evidencing a similar chemical phase for Cu but not for Fe over time. These findings evidence that the intracellular bioprocessing of CuS nanoparticles can reshape them into bioengineered nanostructures without reducing the photothermal function and therapeutic potential.