Self-assembling peptide nanomaterials co-engineered with linoleic acid and catechol motifs for synergistic ferroptosis–photothermal therapy–chemotherapy

The development of nanomaterials with multimodal therapeutic efficacy holds significant promise for advancing cancer treatment. In this study, we designed and synthesized a novel self-assembled nanomaterial from an amphiphilic peptide consisting of a linoleic acid moiety and a catechol group. The amphiphilic peptide could perform self-assembly to form biocompatible nanoparticles in water with targeted cell delivery properties. Through the coordination between catechol groups and Cu²⁺ ions, the amphiphilic peptide encapsulated metal ions and afforded stable hybrid nanoparticles with inherent photothermal activity. Under 808 nm laser irradiation, the photothermal conversion efficiency of LAKDCu hybrid nanoparticles can reach 39.41%. The Cu²⁺ ions within the metal-DOPA complex reacted with endogenous H₂O₂ in cancer cells, generating ROS and depleting GSH. Additionally, the linoleic acid moiety, with its unsaturated double bonds, amplified the generation of lipid peroxides and radicals <i>via</i> free radical chain reactions, rapidly increasing ROS levels and inducing ferroptosis. NIR irradiation further enhanced the catalytic activity of the nanoparticles to promote ROS elevation, GSH depletion, and lipid peroxidation. <i>In vitro</i> experiments demonstrated that the apoptosis rate of 4T1 cells reached 75.7% after LAKDCu combined with photothermal therapy, which was higher than that of the single treatment groups and the control group, thereby enabling multimodal cancer treatment with improved therapeutic efficacy.