Therapeutic Efficacy of a Synthetic Brain-Targeted H₂S Donor Cross-Linked Nanomicelle in Autism Spectrum Disorder Rats through Aerobic Glycolysis

Autism spectrum disorder (ASD) is characterized by cognitive inflexibility and social deficits, with a notably limited range of brain-targeted medications, particularly in the field of nanomedicine. Herein, we introduce the brain-targeted H₂S donor cross-linked nanomicelle, named mannose-PEG600-lipoic acid (Man-LA). Man-LA demonstrates enhanced stability and precise brain delivery by interacting with glucose transporter 1 (GLUT1) in astrocytes, facilitating a gradual release of H₂S that is modulated by glutathione (GSH). <i>In vivo</i>, studies suggest that Man-LA alleviates symptoms of ASD, correlating with increased expression of aerobic glycolysis enzymes, elevated lactate production, and higher H₂S levels, while preventing damage to hippocampal neurons. <i>In vitro</i>, Man-LA tightly binds to aldehyde dehydrogenase family 3 member B1 (<i>Aldh3b1)</i> in astrocytes, upregulating its expression. This interaction promotes aerobic glycolysis and enhances lactate production. These findings suggest a connection between ASD deficits and the dysregulation of astrocytic aerobic glycolysis, underscoring the role of H₂S. Identifying the <i>Aldh3b1</i> gene within aerobic glycolysis pathways provides a promising target for ASD treatment.