Bioengineered Bacterial Membrane Vesicles with Multifunctional Nanoparticles as a Versatile Platform for Cancer Immunotherapy

Inducing immunogenic cell death (ICD) is a critical strategy for enhancing cancer immunotherapy. However, inefficient and risky ICD inducers along with a tumor hypoxia microenvironment seriously limit the immunotherapy efficacy. Non-specific delivery is also responsible for this inefficiency. In this work, we report a drug-free bacteria-derived outer membrane vesicle (OMV)functionalized Fe3O4-MnO2 (FMO) nanoplatform that realized neutrophilmediated targeted delivery and photothermally enhanced cancer immunotherapy. In this system, modification of OMVs derived from Escherichia coli enhanced the accumulation of FMO NPs at the tumor tissue through neutrophil-mediated targeted delivery. The FMO NPs underwent reactive decomposition in the tumor site, generating manganese and iron ions that induced ICD and O2 that regulated the tumor hypoxia environment. Moreover, OMVs are rich in pathogen associated pattern molecules that can overcome the tumor immunosuppressive microenvironment and effectively activate immune cells, thereby enhancing specific immune responses. Photothermal therapy (PTT) caused by MnO2 and Fe3O4 can not only indirectly stimulate systemic immunity by directly destroying tumor cells but also promote the enrichment of neutrophil-equipped nanoparticles by enhancing the inflammatory response at the tumor site. Finally, the proposed multi-modal treatment system with targeted delivery capability realized effective tumor immunotherapy to prevent tumor and recurrence.

Automated summary

In this study, a drug-free bacteria-derived outer membrane vesicle (OMV) functionalized Fe3O4-MnO2 (FMO) nanoplatform was developed for neutrophil-mediated targeted delivery and photothermally enhanced cancer immunotherapy. The modified OMVs enhanced the accumulation of FMO NPs at the tumor site and induced immunogenic cell death (ICD) and regulated the tumor hypoxia environment. Additionally, OMVs effectively activated immune cells and the photothermal therapy (PTT) caused by MnO2 and Fe3O4 stimulated systemic immunity and promoted the enrichment of neutrophil-equipped nanoparticles. This multi-modal treatment system with targeted delivery capability achieved effective tumor immunotherapy and prevention of tumor recurrence.