Kim, Kyoung-Ran Kang, Ji Hee Thai, Hien Bao Dieu Back, Ji Hyun Mao, Chengde Lee, Ji Eun Ko, Young Tag Ahn, Dae-Ro 2024-08-16T04:30:46Z 2024-08-16T04:30:46Z 2024-08-16 2025-06 2366-9608 https://pubs.kist.re.kr/handle/201004/150451 The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics. In vivo, screening of DNA nanostructures yields a cube-shaped structure (D-Cb) as a protein corona-assisted platform for brain delivery of oligonucleotide therapeutics. D-Cb effectively delivers polo-like kinase 1 (PLK-1) antisense oligonucleotides (ASO) to treat glioblastoma in an orthotopic mouse model, demonstrating its potential as a carrier for brain-targeted gene therapy. image English WILEY-V C H VERLAG GMBH Systemic Brain Delivery of Oligonucleotide Therapeutics Enhanced by Protein Corona-Assisted DNA Cubes Article 10.1002/smtd.202400902 1 Small Methods, v.9, no.6 Small Methods 9 6 N scie scopus 001282290300001 2-s2.0-85200107303 Chemistry, Physical Nanoscience & Nanotechnology Materials Science, Multidisciplinary Chemistry Science & Technology - Other Topics Materials Science Article NANOPARTICLES MECHANISMS RECEPTORS TRANSPORT BARRIER glioblastoma multiforme oligonucleotide therapeutics protein corona DNA nanostructures brain delivery