Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease

Mor Sela, Maria Poley, Patricia Mora-Raimundo, Shaked Kagan, Aviram Avital, Maya Kaduri, Gal Chen, Omer Adir, Adi Rozencweig, Yfat Weiss, Ofir Sade, Yael Leichtmann-Bardoogo, Lilach Simchi, Shlomit Aga-Mizrachi, Batia Bell, Yoel Yeretz-Peretz, Aviv Zaid Or, Ashwani Choudhary, Idan Rosh, Diogo CordeiroStav Cohen-Adiv, Yevgeny Berdichevsky, Anas Odeh, Jeny Shklover, Janna Shainsky-Roitman, Joshua E. Schroeder, Dov Hershkovitz, Peleg Hasson, Avraham Ashkenazi, Shani Stern, Tal Laviv, Ayal Ben-Zvi, Avi Avital, Uri Ashery, Ben M. Maoz, Avi Schroeder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.

Original languageEnglish
Article number2304654
JournalAdvanced Materials
Volume35
Issue number51
DOIs
StatePublished - 21 Dec 2023

Keywords

  • Parkinson's disease
  • brain targeting
  • central nervous system
  • lipid nanoparticles
  • neuroinflammation

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