Abstract
Autism spectrum disorder (ASD) presents cognitive and social deficits with a lacking brain-targeted medication landscape, notably in nanomedicine. Here, we introduce a novel brain-targeted H2S donor cross-linked nanomicelles named mannose-PEG600-lipoic acid (Man-LA). Man-LA exhibit enhanced stability and precise brain delivery through interaction with glucose transporter 1 (GLUT1) in astrocytes, facilitating gradual H2S release modulated by glutathione (GSH). In vivo, Man-LA improve symptoms of ASD by correlating with increased expression of aerobic glycolysis enzymes, lactate production, and H2S levels, while also preventing damage to hippocampal neurons. In vitro, Man-LA tightly bind to Aldh3b1 in astrocytes, upregulating its expression and promoting aerobic glycolysis and enhanced lactate production. Collectively, these findings suggest a link between ASD deficits and dysregulated astrocytic aerobic glycolysis, highlighting H2S's role. Notably, the identification of Aldh3b1 gene within aerobic glycolysis pathways presents a promising new target for ASD treatment.