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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.

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The surface functionalization of poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) with various proteolytic enzymes (i.e., trypsin, papain, bromelain) via a two-step carbodiimide coupling method is presented. Depending on the initial Enzyme:NPs ratio, enzyme loadings up to 4.0 wt.%, 4.4 wt.% and 5.34 wt.% were achieved for trypsin, papain and bromelain, respectively. All three conjugated enzymes partially maintained their enzymatic activity after their coupling reaction with the NPs. NPs functionalized with papain and bromelain exhibited a three-fold higher permeability in porcine intestinal mucus compared to nonfunctionalized NPs whereas those conjugated with trypsin showed an almost two-fold higher permeability value. Measurements of the diffusion rates of intestinal mucin, using a nuclear magnetic resonance (NMR) technique, further confirmed these observations, as the enzyme-functionalized NPs were proven to be capable of disrupting the mucin gel structure. According to the reported results, the coupling of proteolytic enzymes to the PLGA NPs' surface largely increases the NPs mucus permeability, thus making it a potentially important mucus permeation strategy.

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