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Brain-Targeted RVG-Liposomal Melatonin Ameliorates Manganese Neurotoxicity by Enhancing Neurogenesis and Modulating

Xueting Wang^1,2, Junge Chen³, Jiao Xia⁴

¹Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing, China.

Journal of Pineal Research

|March 17, 2026

Summary

A novel liposomal melatonin delivery system (MT@RVG-Lip) effectively targets the brain, improving neurogenesis and reducing neuroinflammation caused by manganese exposure. This approach enhances melatonin

Keywords:

RVG amino acid metabolism liposomes melatonin neurogenesis

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Area of Science:

Neuroscience
Toxicology
Biotechnology

Background:

Chronic manganese (Mn) exposure causes neurotoxicity, impairing neurogenesis and metabolic balance.
Melatonin (MT) has neuroprotective effects but suffers from poor bioavailability and limited brain delivery.
Developing targeted delivery systems is crucial for enhancing MT's therapeutic efficacy in neurodegenerative conditions.

Purpose of the Study:

To develop and evaluate a brain-targeted, rabies virus glycoprotein (RVG)-modified liposomal melatonin delivery system (MT@RVG-Lip).
To elucidate the mechanisms underlying MT@RVG-Lip's neuroprotective effects using multi-omics analyses.
To compare the efficacy of MT@RVG-Lip with conventional melatonin and CaNa2EDTA in a mouse model of Mn neurotoxicity.

Main Methods:

Development of RVG-modified liposomes encapsulating melatonin (MT@RVG-Lip).
Multi-omics analyses: brain and intestinal transcriptomics, serum metabolomics, gut metagenomics.
Assessment of neurobehavioral function, neurogenesis, and neuroinflammation in Mn-exposed mice.

Main Results:

MT@RVG-Lip significantly improved motor deficits, enhanced neurogenesis, and reduced neuroinflammation in Mn-exposed mice.
MT@RVG-Lip effectively normalized Mn-disrupted gene expression in neurogenesis regions, particularly those related to amino acid metabolism.
The formulation modulated serum amino acid profiles, intestinal transporter gene expression, and reversed Mn-induced gut dysbiosis, promoting beneficial microbial pathways.

Conclusions:

MT@RVG-Lip demonstrates superior brain-targeting and sustained release, enhancing melatonin's bioavailability and therapeutic outcomes.
The study provides a mechanistic understanding of MT@RVG-Lip's efficacy, highlighting its impact on amino acid metabolism and gut microbiota.
This multifunctional delivery strategy holds significant therapeutic potential for neurodegenerative diseases induced by chronic toxicant exposure.