Targeted Reprogramming of Tumor Cells by Digoxin‐Loaded Immunogenic Nanoparticles Enhances Immunity Against Disseminated Tumor Cells

To potentiate the in situ vaccine effect of radiotherapy (RT), an "inflamed-cell-as-vaccine" strategy is proposed. Specifically, a biomimetic, tumor-targeting nanoparticle (rVAR2-M-NP) carrying a Digoxin-Ovalbumin (Dig-Ova) complex is engineered as its core payload. This nanoparticle-induced gentle immunogenic cell death (ICD) stress promotes self-inflammation in tumor cells without causing direct cytotoxicity. Compared to treatment with Digoxin alone, rVAR2-M-NPs significantly enhance the expression of immunogenic cytokines in tumor cells, effectively suppress hypoxia inducible factor-1α (HIF-1α) expression, and render tumor cells more susceptible to RT without increasing reactive oxygen species (ROS) levels. In both in vitro and in vivo experiments, treatment with rVAR2-M-NPs transform tumor cells into an activated, "inflamed" state, markedly amplifying their immunogenic potential. When integrated with conventional cancer therapies - including surgery, γ-ray irradiation, and anti-PD-1 immunotherapy - the rVAR2-M-NP treatment robustly inhibits primary tumor growth and metastasis in orthotopic 4T1 tumors and significantly improves survival outcomes without notable side effects. Given the increasing interest in leveraging RT-induced in situ vaccination to stimulate systemic antitumor immunity against distant, disseminated, untreated tumors, the findings demonstrate that nanoparticle-delivered immunogens capable of inducing controlled ICD stress can effectively convert tumor cells into a potent cellular nanovaccine, substantially enhancing the therapeutic efficacy of RT-based immunotherapy.