Nose‐to‐Brain Delivery of Acyl‐Ghrelin Peptide Gold Nanoconjugates for Treatment of Neurodegenerative Diseases

Neurodegenerative diseases remain a major therapeutic challenge in aging populations. Acyl-ghrelin, a 28-amino acid gut hormone, demonstrates neuroprotective effects but is limited by instability, rapid clearance, and non-specific distribution when systemically delivered. Nose-to-brain delivery using nanotechnology offers a promising alternative. Gold nanorods (AuNRs), with high therapeutics loading capacity, are proposed as carriers for intranasal acyl-ghrelin delivery. The previous study demonstrates that intranasal AuNRs effectively reach the brain with minimal systemic exposure. This work investigates the feasibility of using acyl-ghrelin gold nanoconjugates to deliver and retain its pharmacological activity through intranasal administration for neurodegenerative diseases. Acyl-ghrelin is conjugated via its C-terminus to hetero-functional polyethylene glycol (PEG) using EDC/sulfo-NHS coupling chemistry, then attached to AuNRs through stable Au─S bonds. Reaction conditions are optimized to minimize multi-PEG substitution, preserving acyl-ghrelin bioactivity and preventing AuNR cross-linking. The resulting nanoconjugates successfully deliver ghrelin to the brain, reaching peak levels at 10 min post-administration with ≈2067.6 ± 760.6 pg g^-1 of brain, a fourfold increase over native expression. Importantly, the peptide retains biological function, as evidenced by AMPK phosphorylation at 30-60 min, a key marker of ghrelin-induced neuroprotection. These findings support intranasal AuNR-mediated delivery of acyl-ghrelin as a promising strategy for treating neurodegenerative diseases.