Dual‐Responsive Nanoreactor Initiates In Situ Generation of Copper Complex for Paraptosis‐Mediated Tumor Chemo‐Immunotherapy

Abstract Paraptosis is a non‐apoptotic and caspase‐independent programmed cell death that can trigger immunogenic cell death (ICD) in tumor cells, representing a potent tactic to overcome immune tolerance to apoptosis. Here, this study demonstrates the construction of a dual‐responsive nanoreactor (MCGDH) to achieve paraptosis‐mediated ICD for chemo‐immunotherapy. Specifically, by doping Cu 2+ into glutathione (GSH)‐responsive dendritic mesoporous silica nanoparticles, the platform (CGDMSN) is endowed with partial acid‐sensitivity. After loaded with 8‐hydroxyquinoline (8‐HQ), cell membrane fragments are coated onto the ammoniated CGDMSN surface to construct MCGDH. Upon internalization by tumor cells, the release of Cu 2+ and 8‐HQ from MCGDH in response to the acidic pH and high concentration of GSH in the tumor microenvironment stimulates in situ generation of Cu(8‐HQ) 2 , inducing tumor cells paraptosis at a low copper dose. Moreover, MCGDH‐mediated paraptosis amplifies the immunogenicity of tumor cells, facilitating antigen presentation to dendritic cells and activating CD8 + /CD4 + T cells immune responses. Furthermore, the combination of MCGDH and anti‐PD‐1 antibodies ( α PD‐1) promotes the systemic anti‐tumor immune responses and long‐term immunological effect to vastly inhibit the primary/distant tumor growth and prevent tumor metastasis. This GSH/pH dual‐responsive nanoreactor serves as a selective platform for accelerating the development of chemo‐immunotherapy.