Engineering blood-brain barrier-permeable and tumor cell-ingestible pro-proteins for glioblastoma treatment

作     者：Xun Liu Wenting Si Ziyin Zhao Ningyu Liu Qiang Yang Renxiang Zhou Rongying Zhu Shanzhou Duan Yongbing Chen Lichen Yin 

作者机构：Institute of Functional Nano and Soft Materials(FUNSOM)Jiangsu Key Laboratory of Carbon-Based Functional Materials and DevicesSoochow UniversitySuzhou 215123China Department of Thoracic SurgeryThe Second Affiliated Hospital of Soochow UniversitySuzhou 215004China 

出 版 物：《Science China Chemistry》 (中国科学（化学英文版）)

年 卷 期：2023年第66卷第9期

页      面：2634-2644页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the Natural Science Foundation of Jiangsu Province (BK20220245) the National Natural Science Foundation of China (52325305, 82241008, 52033006) Jiangsu Key Research and Development Plan (Social Development) Project (BE2020653, BE2021642) the Collaborative Innovation Center of Suzhou Nano Science & Technology the 111 project Suzhou Key Laboratory of Nanotechnology and Biomedicine Joint International Research Laboratory of Carbon-Based Functional Materials and Devices 

主　　题：blood-brain barrier cytosolic protein delivery pro-protein L-type amino acid transporter 1(LAT1) glioblastoma treatment 

摘      要：Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier(BBB) and glioblastoma cell membrane barrier with high efficiency and selectivity. Herein, a unique pro-protein platform was developed via facile green synthesis, which allowed efficient and selective delivery into glioblastoma cells in a carrier-free manner. Pro-proteins were engineered via reversible modification of native proteins in the aqueous buffer with 3,4-dihydroxy-phenylalanine, the substrate of L-type amino acid transporter(LAT1), bridged with a phenylboronic acid-containing linker. By harnessing the LAT1-mediated direct transport mechanism, the optimized pro-protein, named protein-M2-D, can efficiently penetrate BBB after i.v. injection, and subsequently enable selective and endocytosis-free delivery of various proteins including enzymes, toxins, and antibodies into glioblastoma cells, wherein intracellular H_(2)O_(2) triggered traceless restoration of the native protein structure. Systemic administration of saporin-M2-D provoked potent anti-tumor efficacy against orthotopic U87 glioblastoma in mice, without inducing systemic toxicity. Such a facile, versatile, and robust platform renders a promising paradigm for cytosolic protein delivery and glioblastoma treatment.