DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases
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.
Authors
- Jingrui Li (ORCID: https://orcid.org/0000-0001-5906-5114)
- Minghui Cao (ORCID: https://orcid.org/0000-0003-4826-2344)
- Shuo Huang (ORCID: https://orcid.org/0000-0002-3730-8485)
- Gang Ni (ORCID: https://orcid.org/0000-0003-2903-8961)
- Sijin Wu (ORCID: https://orcid.org/0000-0003-4554-4610)
- Chenghao Xuan (ORCID: https://orcid.org/0000-0002-0179-3781)
- Ping Zhou (ORCID: https://orcid.org/0009-0001-3027-1245)
- Yigao Zhu (ORCID: https://orcid.org/0000-0002-3278-4263)
- Jianye Zang (ORCID: https://orcid.org/0000-0003-2648-9783)
- Zhihao Yang (ORCID: https://orcid.org/0000-0001-6186-2024)
- Jun Zhou (ORCID: https://orcid.org/0000-0003-3131-7804)
- Ruixin Ge
- Songbo Xie (ORCID: https://orcid.org/0000-0003-3195-6948)
- Haiyang Yu (ORCID: https://orcid.org/0000-0003-3460-6716)
- Miao Chen (ORCID: https://orcid.org/0000-0002-3538-8231)
- Liang Zhang (ORCID: https://orcid.org/0000-0002-2279-2657)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-2858-0698)
- Qingchao Li (ORCID: https://orcid.org/0000-0002-0307-0085)
- Wei Pan
- Min Liu (ORCID: https://orcid.org/0009-0003-8010-3084)
Institutions
- Shandong University of Technology (CN)
- Nankai University (CN)
- Shandong Normal University (CN)
- Gene Therapy Laboratory (FR)
- Jinan Central Hospital (CN)
- Tianjin Medical University Eye Hospital (CN)
- Shandong First Medical University (CN)
- Tianjin haihe hospital (CN)
- Tianjin Medical University (CN)
- Xi’an Jiaotong-Liverpool University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-60039-2
- Citations
- 9
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- National Natural Science Foundation of China