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殷黎晨教授课题组在Adv. Mater.上发表论文
发布时间:2022-10-06 点击:10

题目:

Endocytosis-Independent and Cancer-Selective Cytosolic Protein Delivery via Reversible Tagging with LAT1 substrate

作者:

Ziyin Zhao1, Xun Liu2, Mengying Hou1, Renxiang Zhou1, Fan Wu1, Jing Yan1, Wei Li1, Yujia Zheng2, Qinmeng Zhong3, Yongbing Chen2, and Lichen Yin1,*

单位:

1Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.

2Department of Thoracic Surgery, Suzhou Key Laboratory of Thoracic Oncologythe Second Affiliated Hospital of Soochow University, Suzhou 215004, China.

3College of Chemistry, Chemical Engineering and Materials Science, Suzhou 215123, China

摘要:

Protein drugs targeting intracellular machineries have shown profound therapeutic potentials, but their clinical utilities are greatly hampered by the lack of efficient cytosolic delivery techniques. Existing strategies mainly rely on nanocarriers or conjugated cell-penetrating peptides (CPPs), which often have drawbacks such as materials complexity/toxicity, lack of cell specificity, and endolysosomal entrapment. Herein, a unique carrier-free approach is reported for mediating cancer-selective and endocytosis-free cytosolic protein delivery. Proteins are sequentially modified with 4-nitrophenyl 4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl) benzyl carbonate as the H2O2 -responsive domain and 3,4-dihydroxy-l-phenylalanine as the substrate of l-type amino acid transporter 1 (LAT1). Thus, the pro-protein can be directly transported into tumor cells by overexpressed LAT1 on cell membranes, bypassing endocytosis and endolysosomal entrapment. In the cytosol, overproduced H2O2 restores the protein structure and activity. Using this technique, versatile proteins are delivered into tumor cells with robust efficiency, including toxins, enzymes, CRISPR-Cas9 ribonucleoprotein, and antibodies. Furthermore, intravenously injected pro-protein of saporin shows potent anticancer efficacy in 4T1-tumor-bearing mice, without provoking systemic toxicity. Such a facile and versatile pro-protein platform may benefit the development of protein pharmaceuticals.

影响因子:

30.849

分区情况:

一区

链接:

https://onlinelibrary.wiley.com/doi/full/10.1002/adma.202110560


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