Targeted degradation of endogenous YAP by nanobody bioPROTAC inhibits tumor progression

Runhua Zhou, Huifang Wang, Gui-Ming Zhang, Yawei Liu, Xiao-Lian Liu, Zhifen Li, Guangwei Shi, Junling Yuan, Chengming Qu, Yang Li, Liang Chen, Jingnan Huang, Hongchao Zhou, Lingyun Dai, Chongzhi Bai, Jigang Wang (), Le Yu (), Zhijie Li () and Yi-Lei Li ()
Additional contact information
Runhua Zhou: Southern Medical University
Huifang Wang: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Gui-Ming Zhang: Southern Medical University
Yawei Liu: Southern Medical University (The First People’s Hospital of Shunde Foshan)
Xiao-Lian Liu: Southern Medical University
Zhifen Li: Shanxi Datong University
Guangwei Shi: Southern Medical University (The First People’s Hospital of Shunde Foshan)
Junling Yuan: Southern Medical University
Chengming Qu: Zhongnan Hospital of Wuhan University
Yang Li: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Liang Chen: Southern Medical University
Jingnan Huang: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Hongchao Zhou: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Lingyun Dai: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Chongzhi Bai: Shanxi Province Hospital of Traditional Chinese Medicine
Jigang Wang: Southern Medical University
Le Yu: Southern Medical University
Zhijie Li: Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)
Yi-Lei Li: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Yes-associated protein (YAP), a key effector of the Hippo pathway, regulates gene expression and promotes tumorigenesis. YAP is conventionally considered “undruggable”, however, targeted protein degradation offers a promising approach to address the challenges associated with targeting this oncogenic protein. In this study, through naïve nanobody phage library screening, we identify multiple nanobodies against human YAP with high affinity and specificity. The YAP nanobody is then fused to the RING domain of RNF4, creating a bio-Proteolysis-Targeting Chimera (bioPROTAC) molecule capable of selectively targeting endogenous YAP for ubiquitin-mediated degradation. Notably, the constructed YAP bioPROTAC demonstrates significant YAP degradation and anticancer efficacy in various YAP-dependent cancers both in vitro and in vivo. Nanoparticles and adeno-associated virus (AAV) can effectively deliver the encoding gene of YAP bioPROTAC, achieving YAP degradation in tumors. Collectively, our study provides a proof-of-concept that the YAP nanobody-bioPROTAC approach can effectively degrade endogenous YAP via the ubiquitin-proteasome system, highlighting a feasible strategy for “undruggable” YAP-dependent cancers.

Date: 2025
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DOI: 10.1038/s41467-025-64426-7

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