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Research Article

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

Shuping Li1,2,§, Xin Li2,§, Jiaqi Meng2, Weier Bao2, Shuang Wang2, Peng Ye2, Xiao-Dong Gao1,2( ), Wei Wei2,3( )
Key Laboratory of Carbohydrate Chemistry and Biotechnology Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China
School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China

§ Shuping Li and Xin Li contributed equally to this work.

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Graphical Abstract

A dynamic shielding strategy was developed to construct a formulation of outer membrane vesicles-cleavable peptide linker-doxorubicin-loaded serum albumin (OMV-cL-AD) for a safe and efficient anti-tumor combination therapy. OMV-cL-AD was cleaved by the over-expressed matrix metalloproteinase (MMP) in the tumor microenvironment (TME) to expose OMVs and release AD, which enabled synergistic tumor inhibition by eliciting OMV-induced immunotherapy to reprogram the immunosuppressive TME and using doxorubicin-induced chemotherapy to kill the tumor cells directly.

Abstract

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.

Keywords

outer membrane vesiclesdoxorubicintumor microenvironmentimmunotherapychemotherapy

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Nano Research
Volume 17 Issue 2,
February 2024
Pages 836-847
DOI: 10.1007/s12274-023-6225-6
Cite this article:
Li S, Li X, Meng J, et al. Dynamic shielding of bacterial outer membrane vesicles for safe and efficient chemo-immunotherapy against tumors. Nano Research, 2024, 17(2): 836-847. https://doi.org/10.1007/s12274-023-6225-6
Topics:
Chemotherapy Nanobiotechnology
Part of a topical collection:
NR45 Awards in Bio-inspired Nanomaterials, 2023

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Received: 04 August 2023
Revised: 20 September 2023
Accepted: 20 September 2023
Published: 17 November 2023
© Tsinghua University Press 2023
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