Self-Assembled Hybrid Nanomaterials from Terpyridine-Pt2⁺-Peptide Complexes for Synergistic NIR-Enhanced Oxidative Stress and Photothermal Therapy in Cancer.

Development of hybrid nanomaterials incorporated with Pt²⁺ complexes with high biocompatibility and multimodal therapeutic activities represents a promising strategy for advancing cancer therapy. Due to the exceptional structural rigidity and metal coordination properties of terpyridine (tpy), we designed and synthesized a novel bioactive molecule with self-assembling abilities by conjugating a tpy moiety with a self-assembling peptide segment. Through noncovalent interactions and Pt²⁺-tpy coordination, this molecule undergoes supramolecular self-assembly to form hybrid nanomaterials with high biocompatibilities with normal cells. The resulting square-planar Pt²⁺-tpy complexes exhibit high binding affinities toward DNA via molecular intercalation and groove binding. Encapsulated Pt²⁺ ions within the nanomaterials also affords them the catalytic activity to create reactive oxygen species (•OH and O₂•⁻) and deplete glutathione (GSH), resulting in oxidative cell death in cancer. Moreover, the coordination between the tpy moiety and Pt²⁺ endows the self-assembled nanomaterials with near-infrared absorption and photothermal heating properties, which enhances therapeutic outcomes by synergistically further augmenting ROS production and GSH scavenging, thereby amplifying apoptotic pathways. Therefore, the multifunctional properties confer highly selective cytotoxicity against cancer cells by inducing oxidative stress-mediated damage, while minimizing harm to normal cells.