A biomimetic nanoplatform for multimodal imaging-guided therapy of esophageal cancer via synergistic activation of cuproptosis and ferroptosis

Esophageal cancer (EC) is a gastrointestinal malignancy with high morbidity and mortality. Traditional treatments yield unsatisfactory outcomes and novel intervention strategy is highly demanded. Cuproptosis and ferroptosis are recently defined modes of cell death, which displays promising utility in cancer treatment. However, their application is hindered due to the tumor inherent antioxidation capacity, absence of tumor-targeting, insufficient efficacy of single mode. To address these limitations, one biomimetic nanoplatform (CM@CDs-Cu 9 S 8 -GOx, CM@CCG) composed of tumor cell membrane (CM), multifunctional carbon dots (CDs), Cu 9 S 8 , glucose oxidase (GOx) is proposed and fabricated. It enabled fluorescence (FL), photothermal (PT), and photoacoustic (PA) imaging-guided EC therapy. MTT, Calcein-AM/PI, flow cytometry and colony formation analysis show that CM@CCG exert high tumor cell proliferation inhibition efficiency (89.98 %). More importantly, in EC xenograft models, it demonstrate excellent EC-targeting and potent tumor inhibition capability (90.44 %). Transcriptomics analysis, immunofluorescence and immunohistochemical staining results show that CM@CCG synergistically activated both cuproptosis via aggregation of lipoylated DLAT and downregulation of FDX1/LIAS expression, and ferroptosis through GPX4 downregulation. Present study leverages nanoplatform endowed with imaging and therapeutic capacity to realize EC therapy by coordinate activation of cuproptosis and ferroptosis. It opens venues for developing novel tumor therapy strategy. • Based on EC clinical samples assay, one multi-functional theranostic nanosystem, CM@CCG, is synthesized for synergistic EC therapy. • CM@CCG exhibits excellent FLI/PTI/PAI multi-modal imaging and antitumor effect. • Mechanistically, CM@CCG activates cuproptosis, ferroptosis and apoptosis to realize the tumor cell killing effect.