Harnessing a Light-Activated Ruthenium(II) Complex Self-Delivery Nanoplatform for Tumor–Organelle Cascade-Targeted Immunotherapy via Type II Immunogenic Cell Death

Abstract Immunogenic cell death (ICD) converts immunosuppressive “cold” tumors into immunogenic “hot” ones, yet ICD inducers with precise tumor–organelle cascade targeting and spatiotemporal controllability remain largely unexplored. Herein, we report a self-delivery nanoplatform (ER-Ru NPs) constructed via the self-assembly of well-defined tumor–endoplasmic reticulum (ER) cascade-targeting ruthenium(II) complexes. The intrinsic amphiphilicity enables self-assembly of the ruthenium(II) complexes into stabilized nanoparticles with efficient tumor accumulation properties via biotin-mediated active targeting, without any exogenous carriers. Following cellular internalization, the released ruthenium(II) complex monomer specifically accumulates in the ER to generate a cleaved Ru–H2O anticancer agent and in situ reactive oxygen species (ROS) upon red-light irradiation. The robust ROS burst triggers severe ER stress via activation of the PERK/eIF2α pathway, leading to the release of damage-associated molecular patterns and the type II ICD induction. Notably, this cascade-targeted ICD activation strategy enhances not only tumor specificity but also the immunogenicity of dying tumor cells, achieving effective primary tumor ablation in the 4T1 models and simultaneously suppressing distant tumors through dendritic cell maturation, cytotoxic T-cell infiltration, and memory T-cell generation. This study offers a paradigm for photoactivatable, self-delivery ICD inducers with cascade targeting, holding substantial promise for clinical translation in precision cancer immunotherapy.