Bacterial Membrane-Derived Dual-Targeted Nanoplatform Enables Synergistic Cuproptosis Induction and Immune Activation for Pancreatic Cancer Therapy

Pancreatic cancer shows limited immune cell infiltration and suboptimal responses to immunotherapy. Notably, dihydrolipoamide S-acetyltransferase (DLAT), a lipoylated mitochondrial protein and key component of the cuproptosis pathway, is highly expressed in pancreatic cancer and positively correlates with PD-L1 levels, supporting a therapeutic strategy that links cuproptosis induction with immune activation. However, most copper ionophores have a short circulating half-life and limited tumor specificity, which reduces copper accumulation in tumor cells and weakens cuproptosis induction. To address these limitations, we developed a bacterial membrane-based, dual-targeted nanosystem (IMPD-L1nb/KAA@ES-Cu NPs) for coordinated delivery of elesclomol–copper (ES-Cu) complex. This platform presents a neutralizing PD-L1 nanobody and a pancreatic tissue-homing peptide (KAA) on bacterial cytoplasmic membranes, enabling increased tumor-specific copper accumulation. The nanosystem enhances cuproptosis-mediated tumor suppression and antigen release, while the membrane-anchored PD-L1 nanobody counters ES-Cu-induced PD-L1 upregulation and blocks immune evasion. Acting as an immunostimulatory agonist, the nanoparticles remodel the immunosuppressive microenvironment by promoting dendritic cell maturation, driving M1 macrophage polarization, and recruiting immune effector cells, including natural killer cells. These effects enhance lymph node trafficking and antigen presentation, ultimately strengthening T cell-mediated tumor eradication. Overall, this nanoplatform couples immunogenic cell death with immune activation, advancing the therapeutic application of cuproptosis in cancer.