Nanobody Engineered and Photosensitiser Loaded Bacterial Outer Membrane Vesicles Potentiate Antitumour Immunity and Immunotherapy

Abstract

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.