Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy.
10.1016/j.apsb.2024.07.020
- Author:
Yiting QIAO
1
;
Miao LUO
2
;
Yufei WANG
2
;
Haoxiang QI
2
;
Menglan WANG
2
;
Yunxin PEI
2
;
Mengqing SUN
2
;
Zhengguo ZHANG
2
;
Jiacheng HUANG
1
;
Pengyu GONG
2
;
Shusen ZHENG
1
;
Jianxiang CHEN
2
Author Information
1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
2. School of Pharmacy, Institute of Hepatology and Metabolic Diseases, Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
- Publication Type:Journal Article
- Keywords:
Bacteria-mediated cancer therapy;
Cancer immune therapy;
Gene delivery;
Interleukin 2;
Tumor immune microenvironment;
Tumor microenvironment;
VNP20009;
ZIF-8
- From:
Acta Pharmaceutica Sinica B
2024;14(12):5418-5434
- CountryChina
- Language:English
-
Abstract:
Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 (Il2) expression plasmid onto the surface of VNP20009, an attenuated Salmonella typhimurium strain with well-documented anti-cancer activity, and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella. Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Salmonella maintained the tumor-targeting feature of bacteria, and could be effectively phagocytosed by intratumoral macrophages, thus leading to the expression and secretion of IL2 in TME. The detailed analysis of tumor immune microenvironment (TIME) showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME, marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME, thus leading to significant anti-tumor effects in melanoma, orthotopic hepatocellular carcinoma, and pulmonary metastasis models. More importantly, Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems. Taken together, we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effective TME-targeted delivery of therapeutic gene, as well as synergistic re-activation of TIME.
