Brain-Targeted RVG-Liposomal Melatonin Ameliorates Manganese Neurotoxicity by Enhancing Neurogenesis and Modulating Systemic Amino Acid Profiles.

Chronic manganese (Mn) exposure induces severe neurotoxicity, characterized by impaired neurogenesis and disrupted metabolic homeostasis. Although melatonin (MT) possesses established neuroprotective properties, its clinical utility is hindered by poor bioavailability and limited brain delivery. Here, we developed a brain-targeted, rabies virus glycoprotein (RVG)-modified liposomal delivery system encapsulating melatonin (MT@RVG-Lip) to enhance therapeutic efficacy. Multi-omics analyses including brain and intestinal transcriptomics, serum metabolomics, and gut metagenomics were conducted to elucidate the underlying mechanisms. MT@RVG-Lip significantly improved motor deficits and enhanced neurogenesis while reducing neuroinflammation in Mn-exposed mice. Compared with regular MT and CaNa2-EDTA, MT@RVG-Lip more effectively alleviated Mn-disrupted gene expression in neurogenesis regions, particularly genes involved in amino acid metabolism. Additionally, MT@RVG-Lip demonstrated a regulatory effect on serum amino acid profiles and intestinal transporter gene expression. Gut microbiota analysis further revealed that MT@RVG-Lip partially reversed Mn-associated dysbiosis and promoted the improvement of key amino acid-related microbiota-mediated metabolic pathways. The RVG-modified liposomal formulation conferred sustained release and improved brain-targeting capability, prolonging MT bioavailability and enhancing therapeutic outcomes. These findings provide a new mechanistic framework for MT-based interventions in neurodegenerative diseases and highlight the therapeutic potential of multifunctional delivery strategies.