Cold plasma triggered cell death with a curcumin and capecitabine loaded magnetic nanocluster-based multifunctional system on the MCF-7 cell line: a smart therapy platform

The development of smart, selective, and multifunctional nanotherapeutics is crucial for advancing next-generation cancer treatments. In this study, superparamagnetic iron oxide nanoclusters (SPIONCs) were coated with mesoporous silica, functionalized with folic acid (FA), and co-loaded with curcumin (CUR) and capecitabine (CAPE) to create a novel nanocarrier system. To enhance cellular internalisation, magnetophoresis was applied before exposure of the cells to cold atmospheric plasma (CAP). The resulting FA-conjugated, CUR and CAPE-loaded nanoclusters were evaluated <i>in vitro</i> in MCF-7 breast cancer and HME-1 normal epithelial cells at varying CAP exposure durations (0, 10, and 20 s) and incubation times (24 and 48 h). This is the first report demonstrating the co-loading of CUR and CAPE into FA-functionalised mesoporous silica-coated magnetic nanoclusters. Drug release studies revealed significantly enhanced release profiles under acidic conditions (pH 5.0 and 6.5), mimicking lysosomal and tumour microenvironments, compared to physiological pH (7.4). Drug-loaded nanoclusters exhibited substantially higher cytotoxicity than the controls with no loading, with a more pronounced effect in MCF-7 cells. Notably, the combined treatment of CAP and CUR-CAPE loaded NCs showed a synergistic cytotoxic effect. IC₅₀ values, after 10 s CAP exposure and 24 h incubation, decreased to 0.43 µg mL^-1 for MCF-7 cells and 37 µg mL^-1 for HME-1 cells. The elevated levels of reactive oxygen species (ROS) induced by CAP played a key role in the observed cytotoxic effects, and both CUR and CAPE were found to enhance this process through ROS-related and potentially additional molecular pathways. These findings highlight the potential of CAP-assisted multicomponent nanocarriers as a promising platform for effective cancer therapy.