Unravelling the cell death mechanism triggered by catalytic copper–iron nanoparticles <i>in vitro</i> and <i>in vivo</i>

Nanomedicine has developed an impressive array of anticancer devices, from drug delivery vectors to hyperthermia-enabling nanoparticles. Lately, emphasis has been shifted to the tumour microenvironment (TME) and to active nanomaterials adapted to the prevailing conditions. Among them, catalytic nanomaterials (also called nanocatalysts) represent a highly interesting alternative, especially when they are able to target metabolites that are present to a greater extent in tumoral cells, opening a window for a catalytically selective action. In this context, herein, we present an in-depth study of the working mechanisms of a <i>meso</i>-2,3-dimercaptosuccinic acid-coated, copper- and iron-based nanoparticle (CuFe@DMSA NPs) with high capability of glutathione (GSH) depletion with simultaneous production of reactive oxygen species (ROS). GSH is an important molecule with antioxidant properties, which is overexpressed in a broad range of tumoral cells, and these CuFe@DMSA NPs catalyse its conversion by means of leached copper ions. In this work, the metabolic action of this nanomaterial on tumoral cells has been thoroughly described, demonstrating that cells underwent a ferroptosis-like cell death, together with the arrest of the cell cycle and induction of apoptosis. The obtained <i>in vitro</i> results were further confirmed <i>in vivo</i>, showing that the increase of apoptosis leads to a significant reduction of tumour growth in treated mice.