PD-L1 nanobody-engineered bacterial outer membrane vesicles delivering cuproptosis micelles for potentiated cancer
Zhimin Li1, Dandan Liang2, Mingge Huo2
1Department of Hematology and Oncology, Taizhou First People's Hospital (Taizhou University Affiliated First People's Hospital), School of Medicine, Taizhou University, Taizhou 318000, PR China; College of Medical Technology, Beihua University, Jilin, 132013, PR China.
Abstract:
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.
