The Francis Crick Institute
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Nanostars carrying multifunctional neurotrophic dendrimers protect neurons in preclinical in vitro models of neurodegenerative disorders.

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journal contribution
posted on 2022-10-27, 09:47 authored by Corinne Morfill, Stanislava Pankratova, Pedro Machado, Nathalie K Fernando, Anna Regoutz, Federica Talamona, Alessandra Pinna, Michal Klosowski, Robert J Wilkinson, Roland A Fleck, Fang Xie, Alexandra E Porter, Darya Kiryushko
A challenge in neurology is the lack of efficient brain-penetrable neuroprotectants targeting multiple disease mechanisms. Plasmonic gold nanostars are promising candidates to deliver standard-of-care drugs inside the brain but have not been trialed as carriers for neuroprotectants. Here, we conjugated custom-made peptide dendrimers (termed H3/H6), encompassing motifs of the neurotrophic S100A4-protein, onto star-shaped and spherical gold nanostructures (H3/H6-AuNS/AuNP) and evaluated their potential as neuroprotectants and interaction with neurons. The H3/H6 nanostructures crossed a model blood-brain barrier, bound to plasma membranes, and induced neuritogenesis with the AuNS, showing higher potency/efficacy than the AuNP. The H3-AuNS/NP protected neurons against oxidative stress, the H3-AuNS being more potent, and against Parkinson's or Alzheimer's disease (PD/AD)-related cytotoxicity. Unconjugated S100A4 motifs also decreased amyloid beta-induced neurodegeneration, introducing S100A4 as a player in AD. Using custom-made dendrimers coupled to star-shaped nanoparticles is a promising route to activate multiple neuroprotective pathways and increase drug potency to treat neurodegenerative disorders.


Crick (Grant ID: 10218, Grant title: Wilkinson, R FC001218)