Salmonella-mediated blood-brain barrier penetration, tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

Chemotherapy is an important adjuvant treatment of glioma, while the efficacy is far from satisfactory, due not only to the biological barriers of blood-brain barrier (BBB) and blood-tumor bar-rier (BTB) but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as up -regulation of P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, glioma targeting, and chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment, including macrophages repolarization and neutrophils infiltration. Specifically, tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/ DOX). By virtue of the surface pathogen-associated molecular patterns derived from native bacteria, OMVs/DOX could be selectively recognized by neutrophils, thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect. Moreover, the P-gp expression on tumor cells was silenced by bacteria type III secretion effector to sensitize the efficacy of DOX, resulting in complete tumor eradication with 100% survival of all treated mice. In addition, the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk, and cardiotoxicity of DOX was also avoided, achieving excellent compatibility. This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

Automated summary

Chemotherapy is a crucial adjuvant therapy for glioma, however, its efficacy is limited by the barriers of blood-brain barrier (BBB) and blood-tumor barrier (BTB), as well as the intrinsic resistance of glioma cells. In this study, a bacteria-based drug delivery strategy was developed to overcome these limitations and achieve targeted glioma therapy. The bacteria selectively colonized the hypoxic tumor region and modulated the tumor microenvironment, enabling the delivery of doxorubicin-loaded bacterial outer membrane vesicles (OMVs/DOX) through neutrophil migration. The OMVs/DOX were selectively recognized by neutrophils, leading to enhanced tumor accumulation and increased efficacy of doxorubicin. The bacteria also silenced the P-glycoprotein expression on tumor cells, resulting in complete tumor eradication and improved survival. The bacteria were subsequently cleared by doxorubicin's antibacterial activity, minimizing the risk of infection and ensuring excellent compatibility.