4.8 Article

Brain-Penetration and Neuron-Targeting DNA Nanoflowers Co-Delivering miR-124 and Rutin for Synergistic Therapy of Alzheimer's Disease

Journal

SMALL
Volume 18, Issue 14, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/smll.202107534

Keywords

blood-brain barrier; microRNAs; nanoparticles; neurodegenerative diseases; RVG29; beta-amyloid

Funding

  1. National Natural Science Foundation of China [81870861, 81471107, 21804144, U1903125, 82073799]
  2. Natural Science Foundation of Hunan province in China [2021JJ31008, 2021JJ20084]
  3. Science and Technology Innovation Program of Hunan Province [2021RC3020]

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Alzheimer's disease (AD) is a common form of dementia in elderly individuals, with no effective treatment currently available. This study presents a novel DNA nanoflowers-based delivery system for AD therapy, which allows exogenous supplementation of miR-124 to ameliorate AD-like pathology. The nanosystem demonstrates promising results in increasing miR-124 levels in the brain and achieving robust therapeutic efficacy in a mouse model of AD.
Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid beta generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.

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