β-Amyloid targeting nanodrug for neuron-specific delivery of nucleic acids in Alzheimer's disease mouse models

Liron L. Israel, Tao Sun, Oliver Braubach, Alysia Cox, Ekaterina S. Shatalova, Harun Mohammad Rashid, Anna Galstyan, Zachary Grodzinski, Xue Ying Song, Oksana Chepurna, Vladimir A. Ljubimov, Antonella Chiechi, Sachin Sharma, Connor Phebus, Yizhou Wang, Julia Y. Ljubimova, Keith L. Black, Eggehard Holler

Research output: Contribution to journalArticlepeer-review

Abstract

Delivery of therapeutic substances into the brain poses a significant challenge in the treatment of neurological disorders. This is primarily due to the blood–brain barrier (BBB), which restricts access, alongside the limited stability and distribution of these agents within the brain tissue. Here we demonstrate an efficient delivery of microRNA (miRNA) and antisense RNA preferentially to neurons compared to astroglia in the brain of healthy and Alzheimer's disease mice, via disulfide-linked conjugation with poly(ß-L-malic acid-trileucine)-copolymer a biodegradable, amphiphilic, and multivalent platform. By conjugating a D-configured (D3)-peptide (vector) for specific targeting, highly efficient delivery across the BBB is achieved through the Low-Density Lipoprotein Receptor-Related Protein-1 (LRP-1) transcytosis pathway, amyloid beta (Aβ) peptides. Nanodrug distribution was determined by fluorescent labeling and analyzed by microscopy in neurons, astroglia, and in extracellular amyloid plaques typical for Alzheimer's disease. Whereas D-configured BBB-vectors can efficiently target neurons, L-configured (e.g., AP2-peptide) guided vector can only cross BBB but not seem to bind neurons. An analysis of post-injection fluorescence distribution, and RNA-seq followed by real-time PCR validation, confirmed a successful in vivo delivery of morpholino-miRNA-186 nanoconjugates into mouse brain. The size and fluorescence intensity of the intracellular nanodrug particulates were analyzed and verified by a competition with non-fluorescent conjugates. Differentially expressed genes (DEGs) from RNA-seq were identified in the nanodrug injected mice, and the changes of selected DEGs related to Alzheimer's disease were further validated by western blot and real-time PCR. Collectively, these results demonstrated that D3-peptide-conjugated nanopolymer drug is able to achieve neuron-selective delivery of miRNA and can serve as an efficient brain delivery vehicle in Alzheimer's disease (AD) mouse models.

Original languageEnglish
Pages (from-to)636-658
Number of pages23
JournalJournal of Controlled Release
Volume361
DOIs
StatePublished - Sep 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • Alzheimer's disease
  • Blood–brain barrier
  • Nanotechnology
  • Neuron targeting
  • Nucleic acid delivery
  • miRNA

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