Engineered bacterial cytoplasmic membranes synergistic delivery of copper complexes induces cuproptosis in pancreatic carcinoma and enhances anti-tumor immunotherapy

Pancreatic cancer is characterized by inadequate immune infiltration and poor response to immunotherapy. The cuproptosis-related protein DLAT, a lipoylated mitochondrial component, is highly expressed in pancreatic tumors and correlates positively with PD-L1 levels, suggesting a promising strategy of combining cuproptosis induction with immune activation. However, existing copper ionophores often suffer from short plasma half-life and poor tumor selectivity, hindering efficient copper delivery and cuproptosis induction. To overcome these limitations, we engineered a bacteria membrane-derived dual-targeted nanosystem (IMPD-L1nb/KAA@PLGA/ES-Cu) for coordinated copper delivery. This system features a PD-L1-blocking nanobody and a pancreatic tumor-homing peptide (KAA) anchored onto bacterial cytoplasmic membranes, enabling precise copper accumulation within tumors. The nanosystem effectively induces cuproptosis-mediated cell death and enhances antigen release, while the membrane-displayed PD-L1 nanobody counteracts ES-Cu-triggered PD-L1 upregulation to prevent immune escape. Acting as a potent immunostimulant, the nanoparticles reprogram the immunosuppressive microenvironment by promoting dendritic cell maturation, polarizing macrophages toward the M1 phenotype, and recruiting effector immune cells such as NK cells. These effects collectively improve lymph node homing and antigen presentation, leading to robust T cell-mediated antitumor immunity. This platform integrates immunogenic cell death with immune activation, highlighting the therapeutic potential of cuproptosis in oncology.