Engineered bacterial outer membrane vesicles encapsulating oncolytic adenoviruses enhance the efficacy of cancer virotherapy by augmenting tumor cell autophagy

Weiyue Ban, Mengchi Sun, Hanwei Huang, Wanxu Huang, Siwei Pan, Pengfei Liu, Bingwu Li, Zhenguo Cheng, Zhonggui He, Funan Liu () and Jin Sun ()
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Weiyue Ban: Shenyang Pharmaceutical University
Mengchi Sun: Shenyang Pharmaceutical University
Hanwei Huang: The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education
Wanxu Huang: Shenyang Pharmaceutical University
Siwei Pan: The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education
Pengfei Liu: The First Hospital of China Medical University, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, China Medical University, Ministry of Education
Bingwu Li: Shenyang Pharmaceutical University
Zhenguo Cheng: Zhengzhou University
Zhonggui He: Shenyang Pharmaceutical University
Funan Liu: Shenyang Pharmaceutical University
Jin Sun: Shenyang Pharmaceutical University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Oncolytic adenovirus (Ad) infection promotes intracellular autophagy in tumors. This could kill cancer cells and contribute to Ads-mediated anticancer immunity. However, the low intratumoral content of intravenously delivered Ads could be insufficient to efficiently activate tumor over-autophagy. Herein, we report bacterial outer membrane vesicles (OMVs)-encapsulating Ads as microbial nanocomposites that are engineered for autophagy-cascade-augmented immunotherapy. Biomineral shells cover the surface antigens of OMVs to slow their clearance during in vivo circulation, enhancing intratumoral accumulation. After entering tumor cells, there is excessive H2O2 accumulation through the catalytic effect of overexpressed pyranose oxidase (P2O) from microbial nanocomposite. This increases oxidative stress levels and triggers tumor autophagy. The autophagy-induced autophagosomes further promote Ads replication in infected tumor cells, leading to Ads-overactivated autophagy. Moreover, OMVs are powerful immunostimulants for remolding the immunosuppressive tumor microenvironment, facilitating antitumor immune response in preclinical cancer models in female mice. Therefore, the present autophagy-cascade-boosted immunotherapeutic method can expand OVs-based immunotherapy.

Date: 2023
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DOI: 10.1038/s41467-023-38679-z

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