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Cationic Lipid-based Intracellular Delivery of Bacterial Effectors for Rewiring Malignant Cell Signaling |
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| Authors: | Shaojun Yang Qiao Tang Long Chen Jin Chang Tian Jiang Jingyi Zhao Prof. Ming Wang Prof. Peng R. Chen |
| Affiliation: | 1. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871 China These authors contributed equally to this work.;2. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing, 100190 China These authors contributed equally to this work.;3. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871 China;4. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences (ICCAS), Beijing, 100190 China |
| Abstract: | The abundance of bacterial effectors have inspired us to explore their potential in rewiring malignant cell signaling. Their incapability for entering cells, however, hinders such application. Herein we developed a cationic lipid-based high throughput library screening platform for effective intracellular delivery of bacterial effectors. As the misregulated MAPK signaling is a hallmark of many types of cancer, we turned to the Shigella effector OspF which irreversibly inactivates ERK, the terminal component of MAPK cascade. We created a function-based screening assay to obtain AMPA-O16B lipid nanoparticles for effective OspF intracellular delivery, which inhibited the malignant MAPK signaling and tumor growth in vitro and in vivo. Furthermore, the optimized lipid nanoparticle formulation can deliver OspF to modulate the immunosuppressive responses in macrophages. Our work is a general strategy to explore the therapeutic potentials of naturally evolved bacterial effectors. |
| Keywords: | bacterial effectors cancer therapy lipid nanoparticle protein delivery signaling rewiring |