Metal-Coordination-Driven Self-Assembly of 8-Hydroxyquinoline-Peptide into Hybrid Nanomaterials for In Vitro Multimodal Synergistic Anticancer Activity

Abstract

Hybrid nanomaterials based on 8-hydroxyquinoline (8-HQ) metal complexes represent a promising class of therapeutic platforms, combining high biocompatibility with diverse pharmacological activities. Leveraging the strong bidentate metal-chelating ability of 8-HQ, we designed and synthesized a bioactive self-assembling molecule (HQD) by conjugating an 8-HQ unit with a peptide assembly motif. Driven by non-covalent interactions and metal-ion coordination (Fe³⁺, Cu²⁺, Mn²⁺), HQD undergoes supramolecular self-assembly in aqueous solution to form hybrid nanomaterials with excellent biocompatibility. While HQDFe and HQDMn exhibit higher photothermal conversion efficiency, HQDCu demonstrates superior multifunctional catalytic activities, including efficient reactive oxygen species (ROS) generation, glutathione (GSH) depletion, and DNA cleavage via intercalation and groove binding. Additionally, the strong near-infrared absorption and efficient photothermal effect of HQDCu further disrupt redox homeostasis, amplify oxidative stress, and promote cancer cell apoptosis. Importantly, doxorubicin-loaded HQDCu nanoparticles (HQDCuD) enhance cellular uptake and exert potent antitumor efficacy through the synergistic integration of chemotherapy, photothermal therapy, and ROSmediated oxidative damage, establishing a powerful multimodal platform for cancer treatment.