RT Journal Article
T1 Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases
A1 Samaridou, Eleni
A1 Walgrave, Hannah
A1 Salta, Evgenia
A1 Moreira Álvarez, David
A1 Castro López, Vanessa
A1 Loza García, María Isabel
A1 Alonso Fernández, María José
K1 Nose-to-Brain administration
K1 Brain delivery
K1 Nanocomplex
K1 Cell-penetrating peptide
K1 Octaarginine
K1 miRNA
AB Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol - polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's disease
PB Elsevier
SN 0142-9612
YR 2020
FD 2020
LK http://hdl.handle.net/10347/23901
UL http://hdl.handle.net/10347/23901
LA eng
NO Biomaterials. Volume 230, February 2020, 119657. https://doi.org/10.1016/j.biomaterials.2019.119657
NO This document is the preprint manuscript version of a published work that appeared in final form in Biomaterials, © 2019Elsevier Ltd. after peer review and technical editing by the publisher. To access the final edited and published work see:https://doi.org/10.1016/j.biomaterials.2019.119657
NO The work was supported by the European B-Smart Consortium, which received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 721058
DS Minerva
RD 27 abr 2026