DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases

Ruixin Ge, Miao Chen, Sijin Wu, Sirui Huang, Ping Zhou, Minghui Cao, Fan Zhang, Jinzhi Zang, Yigao Zhu, Jingrui Li, Guilin Ni, Zhihao Yang, Qingchao Li, Wei Pan, Liang Zhang, Min Liu, Chenghao Xuan, Haiyang Yu (), Jun Zhou () and Songbo Xie ()
Additional contact information
Ruixin Ge: Shandong Normal University
Miao Chen: Shandong University of Technology
Sijin Wu: Xi’an Jiaotong-Liverpool University
Sirui Huang: Tianjin Medical University
Ping Zhou: Shandong Normal University
Minghui Cao: Shandong Normal University
Fan Zhang: Shandong Normal University
Jinzhi Zang: Shandong Normal University
Yigao Zhu: Shandong Normal University
Jingrui Li: Shandong University of Technology
Guilin Ni: Xi’an Jiaotong-Liverpool University
Zhihao Yang: Tianjin Medical University
Qingchao Li: Shandong Normal University
Wei Pan: Shandong Normal University
Liang Zhang: Jinan Central Hospital Affiliated to Shandong First Medical University
Min Liu: Haihe Laboratory of Cell Ecosystem
Chenghao Xuan: Tianjin Medical University
Haiyang Yu: South San Francisco
Jun Zhou: Shandong Normal University
Songbo Xie: Tianjin Medical University General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Oligonucleotide-based medicine faces challenges in efficiently crossing the blood-brain barrier and rapidly reducing toxic proteins. To address these challenges, here we establish an integrated modality, brain-penetrant DNA nanoflowers incorporated with oligonucleotide-based proteolysis targeting chimeras. Using FUS as a proof-of-concept, mutations of which cause frontotemporal dementia and amyotrophic lateral sclerosis, we demonstrate that a FUS-engaging RNA oligonucleotide crosslinked to a ligand for Cereblon efficiently degrade FUS and its cytoplasmic disease-causing mutants through a ubiquitin-proteasomal pathway. The DNA nanoflower contains hundreds of oligonucleotide binding sites and transferrin receptor-engaging aptamers, allowing efficient loading of the oligonucleotide-based degrader and engaging transferrin receptors for brain delivery. A single dose intravenous injection of this modality reaches brain parenchyma within 2 h and degrades 80% FUS protein there, sustained for two weeks without noticeable toxicity. DNA nanoflower oligonucleotide-based degrader is a therapeutic strategy for neurodegenerative diseases that leverages the advantages of designer oligonucleotides and targeted protein degradation.

Date: 2025
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DOI: 10.1038/s41467-025-60039-2

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