Multimodal Phototherapy- and Ferroptosis-Enhanced Ga(III) Supramolecular Nanomicelle for Tumor Theranostics

Self-assembled nanomedicines for clinical tumor therapy still face major limitations. Here, a multimodal theranostic platform is constructed based on a hierarchically assembled supramolecular nanomicelle with a Ga(III)-core. Compared with indocyanine green, the metal-organic dye Cy71-Ga offers superior near-infrared absorption/emission, enhanced reactive oxygen species generation, and a high photothermal conversion efficiency (PCE, 24.81%). Notably, Cy71-Ga downregulates xCT and CD98, thereby markedly reinforcing ferroptosis in tumor cells at the source. Additionally, CPT-HA, formed by conjugating camptothecin with sodium hyaluronate, encapsulates Cy71-Ga via electrostatic interaction and hydrophobic interactions, yielding nanomicelle Cy71-Ga NPs capable of precise targeted delivery. Cy71-Ga NPs also enable fluorescence and photothermal imaging of mouse tumors, thereby triggering immunogenic cell death, activating cytotoxic CD8⁺ T cells, and promoting tumor cell apoptosis via perforin release under laser irradiation. Furthermore, Cy71-Ga NPs can disrupt glutathione synthesis and significantly enhance ferroptosis under laser irradiation. In general, this multimodal theranostic approach includes phototherapy, ferroptosis, chemotherapy of camptothecin, and immunotherapy, achieves an exceptional 83.85% tumor suppression rate in vivo and effectively prevents tumor metastasis.