Peptidomimetic-liganded gold nanoclusters for controlled iron delivery and synergistic suppression of tumor growth

A novel peptidomimetic-liganded gold nanocluster (CDp-AuNC) is proposed for the synergistic suppression of tumor growth. Taking advantages of the multi-capabilities offered by the surface ligands, including iron chelation, glutathione peroxidases-1 (GPx-1) binding, and tumor cells recognition, CDp-AuNCs are able to function as the nanocarriers to deliver iron in a controlled manner for the ferroptosis therapy and as the inhibitors for GPx-1 to induce the apoptosis of tumor cells. The Fe²⁺@CDp-AuNC nanocomplexes are fabricated through a facile self-assembly method. The experimental data verify that the nanocomplexes are internalized specifically by tumor cells with high efficiency. The acidic microenvironment in endosomes triggers the collapse of the nanocomplexes and thereby releases Fe²⁺ to induce ferroptosis and CDp-AuNCs to inhibit the enzyme activity of GPx-1. Benefiting from the H₂O₂-depleted pathway inhibition and ferroptosis acceleration, the intracellular reactive oxygen species (ROS) level could be enhanced significantly. As a consequence, the apoptosis/ferroptosis of 4T1 cells as well as the tumor elimination in vivo are observed after treatment with the Fe²⁺@CDp-AuNC nanocomplexes at a relatively low dose. The facile iron loading method, simple construction procedure, and outstanding tumor suppression performance, provide CDp-AuNCs great application promise. More importantly, the strategy of peptidomimetic ligands design provides a transferable approach to building multifunctional nanomaterials.