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Acyl\u2010ghrelin, a 28\u2010amino acid gut hormone, demonstrates neuroprotective effects but is limited by instability, rapid clearance, and non\u2010specific distribution when systemically delivered. Nose\u2010to\u2010brain delivery using nanotechnology offers a promising alternative. Gold nanorods (AuNRs), with high therapeutics loading capacity, are proposed as carriers for intranasal acyl\u2010ghrelin delivery. The previous study demonstrates that intranasal AuNRs effectively reach the brain with minimal systemic exposure. This work investigates the feasibility of using acyl\u2010ghrelin gold nanoconjugates to deliver and retain its pharmacological activity through intranasal administration for neurodegenerative diseases. Acyl\u2010ghrelin is conjugated via its C\u2010terminus to hetero\u2010functional polyethylene glycol (PEG) using EDC\/sulfo\u2010NHS coupling chemistry, then attached to AuNRs through stable Au\u2500S bonds. Reaction conditions are optimized to minimize multi\u2010PEG substitution, preserving acyl\u2010ghrelin bioactivity and preventing AuNR cross\u2010linking. The resulting nanoconjugates successfully deliver ghrelin to the brain, reaching peak levels at 10 min post\u2010administration with \u22482067.6 \u00b1 760.6 pg\u00a0g\n                    <jats:sup>\u22121<\/jats:sup>\n                    of brain, a fourfold increase over native expression. Importantly, the peptide retains biological function, as evidenced by AMPK phosphorylation at 30\u201360 min, a key marker of ghrelin\u2010induced neuroprotection. These findings support intranasal AuNR\u2010mediated delivery of acyl\u2010ghrelin as a promising strategy for treating neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1002\/smll.202504517","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T06:13:46Z","timestamp":1753078426000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Nose\u2010to\u2010Brain Delivery of Acyl\u2010Ghrelin Peptide Gold Nanoconjugates for Treatment of Neurodegenerative Diseases"],"prefix":"10.1002","volume":"21","author":[{"given":"Shunping","family":"Han","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science Faculty of Life Sciences &amp; Medicine King's College London Franklin\u2010Wilkins Building  150 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rifka N.","family":"Utami","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science Faculty of Life Sciences &amp; Medicine King's College London Franklin\u2010Wilkins Building  150 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Qin","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science Faculty of Life Sciences &amp; Medicine King's College London Franklin\u2010Wilkins Building  150 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revadee","family":"Liam\u2010Or","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science Faculty of Life Sciences &amp; Medicine King's College London Franklin\u2010Wilkins Building  150 Stamford Street London SE1 9NH 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