Dynamic shielding of bacterial outer membrane vesicles for safe and efficient chemo-immunotherapy against tumors

Bacterial outer membrane vesicles (OMVs) are potent immunostimulants of regulating the tumor microenvironment (TME) for immunotherapy, and can be used to deliver drugs. However, the severe systemic inflammatory response triggered by OMVs upon intravenous (i.v.) injection has limited their application. Here, we developed a safe and effective strategy by conjugating doxorubicin-loaded serum albumin (SA-DOX, AD) onto the surface of OMVs using a matrix metalloproteinase (MMP)-cleavable peptide linker (cL). This approach enabled the dynamic shielding of OMVs to reduce the systemic side effects while simultaneously enhancing the anti-tumor effects through chemo-immunotherapy. Specifically, the resulting OMV-cL-AD formulation exhibited significantly enhanced accumulation at the tumor site after i.v. administration, facilitated by the SA decoration on the OMVs surface. Subsequently, the shield on the OMV-cL-AD was cleaved by the over-expressed MMP in the TME, leading to the release of both OMVs and AD. This process provided OMV-induced immunotherapy and DOX-induced chemotherapy, resulting in synergistic tumor inhibition. In conclusion, our work demonstrated the potential of OMV-cL-AD as an effective immunochemotherapy strategy that can prolong the survival time of mice without inducing side effects.