Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy

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外文摘要：Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward 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 typhimur-ium 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@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral 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 effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.

外文关键词：

Bacteria-mediated cancer therapyVNP20009ZIF-8Gene deliveryTumor microenvironmentTumor immune microenvironmentInterleukin 2Cancer immune therapy

作者：

Yiting Qiao、Miao Luo、Yufei Wang、Haoxiang Qi、Menglan Wang、Yunxin Pei、Mengqing Sun、Zhengguo Zhang、Jiacheng Huang、Pengyu Gong、Shusen Zheng、Jianxiang Chen

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作者单位：

Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China

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

Jinan Microecological Biomedicine Shandong Laboratory,Jinan 250000,China

NHC Key Laboratory of Combined Multi-organ Transplantation,Key Laboratory of Organ

Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province,Dian Diagnostics Group Co.,Ltd.,Hangzhou 310000,China

NHC Key Laboratory of Combined Multi-organ Transplantation,Key Laboratory of Organ Transplantation,Hangzhou 310003,China

Key Laboratory of the Diagnosis and Treatment of Organ Transplantation,Research Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic Cancer,Chinese Academy of Medical Science(2019RU019),Hangzhou 310003,C

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出版年：

2024

DOI：

10.1016/j.apsb.2024.07.020

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(12)