PD-L1 nanobody-engineered bacterial outer membrane vesicles delivering cuproptosis micelles for potentiated cancer immunotherapy

Immune checkpoint inhibitors (ICIs) have emerged as a transformative approach in Cancer treatment, yet their efficacy is often limited by low response. Cuproptosis is a novel form of regulated cell death with lipoylated protein aggregation and iron‑sulfur (FeS) cluster protein destabilization. Here, we fabricated a PD-L1 nanobody-engineered Bacterial outer membrane vesicles (OMVs) delivering elesclomol (ES) micelles for enhanced immunotherapy in triple-negative breast Cancer (TNBC). By decorating OMVs with PD-L1 nanobodies, we enhance the tumor-targeting delivery efficiency of Cuproptosis nanoinducers and PD-L1 blockade capability. Simultaneously, the engineered OMVs delivering ES micelles exhibited enhanced cytotoxicity against breast Cancer cells via inducing cuproptotic cell death. In mice bearing 4 T1 xenografts, OMV-PD-L1nb@ES demonstrated significant tumor growth suppression. Notably, our nanoparticles elicited a robust antitumor immune response with increased infiltration and activation of CD8⁺ T cells and Treg depletion. By integrating cuproptotic tumor death with immune checkpoint blockade, the dual-functional nanoplatform represents a promising strategy for potentiated immunotherapy.

Cancer immunotherapy; Cuproptosis; Drug delivery; Immune checkpoint inhibitor; Outer membrane vesicle.