A flaxseed oil body-based delivery system integrating calcium overload and lipid peroxidation for immunogenic cell...

Hepatocellular carcinoma (HCC) is a highly lethal malignancy characterized by limited immunogenicity and poor responsiveness to immunotherapy, highlighting the urgent need for effective strategies to enhance antitumor immune activation. Herein, we designed a flaxseed-derived natural oil bodies (FOBs)-based nanoplatform, Cur/FOBs@CaP, as an immunogenic cell death (ICD) amplifier for HCC immunotherapy. FOBs were extracted and serve as biocompatible carriers for curcumin (Cur) and calcium phosphate (CaP) loading, while simultaneously acting as intrinsic depots of polyunsaturated fatty acids (PUFAs). Upon cellular internalization, Ca²⁺ released from Cur/FOBs@CaP synergizes with Cur to induce pronounced intracellular calcium overload, leading to mitochondrial dysfunction and oxidative stress. Meanwhile, sustained PUFAs supply drives continuous lipid peroxidation, which cooperates with calcium overload to further amplify oxidative stress damage. The coordinated calcium overload and lipid peroxidation-mediated oxidative stress robustly induce ICD. Consequently, Cur/FOBs@CaP treatment effectively promotes dendritic cell maturation, enhances T cell activation, and elicits durable antitumor immune responses. In murine HCC models, Cur/FOBs@CaP induces marked tumor regression and immune remodeling. Moreover, in combination with anti-PD-L1 therapy, Cur/FOBs@CaP elicits potent systemic antitumor immunity. In a pulmonary metastasis model, inhalation administration of Cur/FOBs@CaP significantly suppresses lung metastatic lesions. Overall, this study demonstrates a metabolism-oriented nanoplatform that coordinates calcium dysregulation and lipid peroxidation amplification to enhance ICD-based immunotherapy in HCC.