Massive Intracellular Remodeling of CuS Nanomaterials Produces Nontoxic Bioengineered Structures with Preserved Photothermal Potential

Abstract

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.

In Vivo Assimilation of CuS, Iron Oxide and Iron Oxide@CuS Nanoparticles in Mice: A 6-Month Follow-Up Study

“…These data indicate that the administered NPs had no impact on the overall metabolism of the mice in the long term. This correlates nicely with previous analyses performed in vitro that showed an adaptation of the cellular metabolism to these nanomaterials with no toxicity reported, even at higher doses [28].…”

“…The nanoparticles investigated here were previously reported by our team for their theranostics properties [10,28]. All details about the synthesis steps can be found there.…”

“…The surface of all nanoassemblies was PEGylated by the addition of PEG-SH (final concentration 10 mg/mL) under shaking overnight at 4 • C and subsequent washing by centrifugation. In depth characterization of the nanoparticles obtained (HR-TEM, EELS, UV-Vis-NIR spectra, photothermal conversion parameter) are included in previous works [10,28]. Additional transmission electron microscopy characterization using a JEOL-1011 microscope operating at 100 kV is shown in Figure S1.…”

“…In this case, the iron oxide@CuS hydrids were subjected to three stimuli: magnetic hyperthermia (MHT), photothermia (PTT), and photodynamic therapy (PDT), that altogether induced tumor regression via the production of heat and reactive oxygen species (ROS). We also explored the fate of such nanostructures in the biological environment in vitro, and reported low toxicity [28]. Interestingly, both CuS and iron oxide@CuS NPs could be biologically reshaped while preserving their photothermal efficiency.…”

CuS@BSA-NB2 Nanoparticles for HER2-Targeted Photothermal Therapy

“…With the diversification of treatment methods, it is also more popular to use CuS as the basic carrier to wrap or to modify other materials to synthesize more new therapeutic agents to treat tumors (Gao et al, 2018;Curcio et al, 2021). For example, Li et al (Li et al, 2021) synthesized CuS@MnO/HA NPs, and they used CuS to co-load doxorubicin (DOX) and indocyanine green (ICG) to induce photothermal effects, and HA modification to endow the system with CD44 receptormediated tumor-targeting properties.…”