Chemotherapy Mediated by Biomimetic Polymeric Nanoparticles Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

Abstract Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long‐term antitumor immunity still remains to be an extreme challenge. Herein, the design of an advanced redox‐responsive nanomedicine formulation based on phosphorus dendrimer–copper(II) complexes (1G₃‐Cu)‐ and toyocamycin (Toy)‐loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM) are reported. The designed GCT@CM NPs with a size of 210 nm are stable under physiological conditions but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co‐loading of 1G₃‐Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G₃‐Cu‐induced mitochondrial dysfunction and Toy‐mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor‐infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G₃‐Cu render the GCT@CM NPs with homotypic targeting and T₁‐weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP‐mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy‐potentiated immunotherapy of different tumor types through different mechanisms or synergies.