Blood-brain barrier-penetrating Angiopep-2/Sirtuin 1 nanoparticles rescue sevoflurane neurotoxicity through multi-omics identified necroptosis pathways.

Developmental neurotoxicity (DNT) induced by sevoflurane exposure poses significant risks to pediatric anesthesia, yet effective protective strategies remain limited. Here, we developed self-assembling Angiopep-2/SIRT1 nanoparticles (Ang/SIRT1-NPs) with favorable biocompatibility and brain-targeting properties. Through in vitro and in vivo studies, we demonstrate that Ang/SIRT1-NPs effectively alleviate sevoflurane-induced neuronal apoptosis, neuroinflammation, and dendritic spine loss. Multi-omics analyses identified SIRT1-mediated suppression of necroptosis and oxidative stress pathways as key mechanisms underlying neuroprotection. Behavioral assays further confirmed improved cognitive and motor function in nanoparticle-treated mice. Our findings highlight the potential of Ang/SIRT1-NPs as a promising neuroprotective strategy for preventing anesthesia-related DNT and support their translational application in pediatric neuroprotection.