Nanobody engineered and photosensitiser loaded bacterial outer membrane vesicles potentiate anti-tumor immunity and immunotherapy

Bacterial outer membrane vesicles (OMVs) are promising as antitumor agents, but their clinical application is limited by toxicity concerns and unclear mechanisms. We engineered OMVs with CDH17 tumor-targeting nanobodies, enhancing tumor 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 tumor-associated macrophages (TAMs). Loading engineered OMVs with photoimmunotherapy photosensitizers further enhanced tumor inhibition and STING activation in TAMs. Combining nanobody-engineered OMV-mediated photoimmunotherapy with CD47 blockade effectively suppressed primary and metastatic tumors, establishing sustained antitumor 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 tumor immunotherapy, offering a promising approach to overcome current limitations in cancer treatment.