biostudies-literatureGe RNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)4683https://www.ebi.ac.uk/biostudies/studies/S-EPMC12092677biostudies-literatureUnknown16(1)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 degrNature communicationsDNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases.PMC120926773220061332270892Zhang FPan WCao MLi JZhou PZhu YLiu MXuan CChen MNi GLi QZhang LYu HXie SGe RHuang SYang ZZang JWu SZhou JfalseDNA 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 degr2025-01-01T00:00:00Z2025 May2026-06-01T05:21:00.652Z2026-04-08T09:30:26.943ZS-EPMC120926774039404610.1038/s41467-025-60039-2