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

Abstract 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.