Bacterial outer membrane vesicles (OMVs) are promising as antitumour agents, but their clinical application is limited by toxicity concerns and unclear mechanisms. We engineered OMVs with cadherin 17 (CDH17) tumour-targeting nanobodies, enhancing tumour selectivity and efficacy while reducing adverse effects. These engineered OMVs function as natural stimulator of interferon genes (STING) agonists, activating the cyclic GMP-AMP synthase (cGAS)-STING pathway in cancer cells and tumour-associated macrophages (TAMs). Loading engineered OMVs with photoimmunotherapy photosensitisers further enhanced tumour inhibition and STING activation in TAMs. Combining nanobody-engineered OMV-mediated photoimmunotherapy with CD47 blockade effectively suppressed primary and metastatic tumours, establishing sustained antitumour immune memory. This study demonstrates the potential of nanobody-engineered OMVs as STING agonists and provides insights into novel OMV-based immunotherapeutic strategies harnessing the innate immune system against cancer. Our findings open new avenues for OMV applications in tumour immunotherapy, offering a promising approach to overcome current limitations in cancer treatment.
Keywords: CDH17; STING pathway; bacterial outer membrane vesicle; nanobody; photoimmunotherapy; tumour‐associated macrophages.
© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.