Application of an intercellular adhesion molecule-1-targeted nanoparticles loaded with irisin in postoperative neurocognitive disorder through metabolic axis activation and barrier restoration.

Postoperative neurocognitive disorder (PND) is a frequent complication in elderly surgical patients and is closely associated with blood-brain barrier (BBB) disruption and cerebral metabolic imbalance. The present study explores a metabolism-based therapeutic strategy using an Irisin nanoparticle delivery system to restore postoperative cerebral energy homeostasis, repair BBB integrity, and mitigate neuroinflammation and cognitive impairment. In a PND mouse model, an Intercellular adhesion molecule-1-targeted nanoparticle loaded with Irisin (ICAM-1-NP@Irisin) was evaluated. Targeted delivery enabled preferential accumulation of Irisin within postoperative inflammatory endothelium, resulting in enhanced tight junction protein expression, increased cerebral ATP levels, and improved cognitive performance. Mechanistic analyses demonstrated activation of the AMPK/PGC-1α/SIRT1/UCP2 metabolic axis, which promoted endothelial repair while suppressing glial activation and neuronal apoptosis. Integrated multi-omics profiling revealed expansion of reparative endothelial cell subpopulations, supporting a regulatory framework linking metabolism, barrier connectivity, and cognition. Collectively, these findings identify ICAM-1-NP@Irisin as a promising brain-protective strategy for PND that integrates metabolic modulation with precision nanodelivery, offering translational insights into postoperative brain dysfunction.