Engineered tumor-symbiotic bacterial membrane nanovesicles enable precise immuno-chemotherapy of colorectal cancer

Abstract

Gut microorganisms show promising therapeutic effects and drug delivery potential for colorectal cancer (CRC) treatment, but are limited by their insufficient targeting ability and side effects. Fusobacterium nucleatum (Fn) is a key symbiotic bacterium in CRC, which can preferentially accumulate in tumor tissues and invade tumor cells, while its tumorigenicity restricts the application in drug delivery. Herein, we engineered Fn with anchored PD-L1 antibody (αPD-L1), and then isolated the Fn membranes to construct bacterial membrane nanovesicles (ab-FMNVs) for precise delivery of chemotherapeutic drugs. The ab-FMNVs exploited Fn's inherent tumor colonization capabilities to achieve tumor-targeted delivery through the specific membrane protein FadA-mediated pathway, and modulated the PD-L1 immune checkpoint pathway for tumor immunotherapy. Simultaneously, ab-FMNVs were internalized into CT26 cells to release the chemotherapeutic agent doxorubicin, synergistically inhibiting tumor cell proliferation and metastasis. In a CRC-bearing mouse model, doxorubicin-loaded ab-FMNVs increased tumor accumulation and demonstrated superior antitumor efficacy against both primary and recurrent CRC progression without inducing any side effects. This innovative approach holds promise for precision cancer therapies by harnessing the symbiotic relationship between bacteria and CRC.