TY - JOUR
T1 - DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases
AU - Ge, Ruixin
AU - Chen, Miao
AU - Wu, Sijin
AU - Huang, Sirui
AU - Zhou, Ping
AU - Cao, Minghui
AU - Zhang, Fan
AU - Zang, Jinzhi
AU - Zhu, Yigao
AU - Li, Jingrui
AU - Ni, Guilin
AU - Yang, Zhihao
AU - Li, Qingchao
AU - Pan, Wei
AU - Zhang, Liang
AU - Liu, Min
AU - Xuan, Chenghao
AU - Yu, Haiyang
AU - Zhou, Jun
AU - Xie, Songbo
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=105005530974&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-60039-2
DO - 10.1038/s41467-025-60039-2
M3 - Article
AN - SCOPUS:105005530974
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4683
ER -