Copper/iron-based intelligent nanoparticles self-amplify apoptosis/ferroptosis/cuproptosis in colorectal cancer

To address the key challenge of insufficient chemosensitivity in colorectal cancer treatment due to apoptosis resistance, this study proposes a "multi-pathway synergistic killing" strategy that enhances anti-tumour efficacy by simultaneously activating multiple cell death pathways, including apoptosis, ferroptosis, and cuproptosis. Utilising a cRGD targeting peptide, ferrocenecarboxylic acid (Fc), camptothecin (CPT), and doxorubicin (DOX), four amphiphilic molecules were designed and synthesised, which were further assembled and chelated with copper ions to construct multifunctional nanoparticles, cRDT@FC. These nanoparticles can efficiently accumulate in tumour regions. The disulphide bonds and Cu²⁺ within them jointly consume the high concentration of glutathione (GSH) in cells, leading to the disintegration of the nanostructure and the release of CPT, thereby achieving the desired chemotherapy effects. Meanwhile, Cu²⁺ is reduced by GSH to Cu⁺, which, in synergy with Fe²⁺ in the system, catalyses the Fenton reaction to generate a large amount of hydroxyl radicals (·OH) achieving chemodynamic therapy (CDT), significantly enhancing the oxidative stress level and thereby synergistically inducing ferroptosis and cuproptosis. This study presents a novel approach to developing multi-mode cell death synergistic treatment strategies utilising nanotechnology.