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<p>Oligonucleotide-based medicine faces challenges in efficiently crossing the&#xa0;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&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月20日

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  • 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,
  • Songbo Xie

摘要

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.