内吞作用
胞浆
皂甙
纳米载体
癌细胞
生物化学
细胞生物学
生物
细胞
药物输送
酶
细胞毒性
癌症
材料科学
纳米技术
免疫毒素
遗传学
体外
作者
Ziyin Zhao,Xun Liu,Mengying Hou,Renxiang Zhou,Fan Wu,Jing‐Kun Yan,Wei Li,Yujia Zheng,Qinmeng Zhong,Yongbing Chen,Lichen Yin
标识
DOI:10.1002/adma.202110560
摘要
Abstract 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‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl) benzyl carbonate as the H 2 O 2 ‐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 H 2 O 2 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.
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