文献类型：期刊文献

英文题名：Targeting intracellular cancer proteins with tumor-microenvironment-responsive bispecific nanobody-PROTACs for enhanced therapeutic efficacy

作者：Deng, Changping[1,2];Ma, Jiacheng[3];Liu, Yuping[4];Tong, Xikui[1];Wang, Lei[1];Dong, Jiayi[1];Shi, Ping[1];Wang, Meiyan[5];Zheng, Wenyun[4];Ma, Xingyuan[1]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[2]Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, Shanghai, Peoples R China;[3]Chinese Univ Hong Kong, Dept Informat Engn, Hong Kong, Peoples R China;[4]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, POB 365,130 Meilong Rd, Shanghai 200237, Peoples R China;[5]Shanghai Univ, Sch Med, Shanghai, Peoples R China

年份：2025

卷号：6

期号：2

外文期刊名：MEDCOMM

收录：WOS:【ESCI(收录号:WOS:001398906400001)】；

基金：We are grateful to the Public Instrument Service Platform of the State Key Laboratory of Bioreactor Engineering for their invaluable support during this research endeavor. The National Key Research and Development Project of China (2018YFA0902800); the Postdoctoral Fellowship Program of CPSF (GZC20231596) and National Natural Science Foundation (32471003).

语种：英文

外文关键词：nanobody; PD-L1 and Survivin; proteolysis targeting chimeras (PROTACs); targeted degradation; tumor microenvironment

摘要：Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, their non-specificity can lead to systemic toxicity due to protein degradation in normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged the tumor microenvironment to enhance drug specificity. In this study, we engineered BumPeD, a novel bispecific nanobody-targeted PROTACs-like platform, by fusing two nanobodies with a Furin protease cleavage site (RVRR) and a degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling the tumor microenvironment to direct the degradation of intracellular proteins. We utilized KN035 and Nb4A to target PD-L1 (programmed death ligand 1) on the cell surface and intracellular Survivin, respectively. In vitro experiments showed that BumPeD triggers Survivin degradation via the ubiquitin-proteasome pathway, inducing tumor apoptosis and suppressing bladder tumor cell proliferation and migration. In vivo experiments further confirmed BumPeD's robust anti-tumor efficacy, underscoring its potential as a precise protein degradation strategy for cancer therapy. Our platform provides a systematic approach to developing effective and practical protein degraders, offering a targeted theoretical basis and experimental support for the development of novel degradative drugs, as well as new directions for cancer therapy.