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

Abstract 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.