Brain-targeting lipid nanoparticles of nicotinamide mononucleotide: preparation, optimization, and characterization

Nicotinamide mononucleotide (NMN) has anti-inflammatory, antioxidant, and mitochondrial function-enhancing properties, which demonstrate its significant neuroprotective potential. However, its high water solubility presents challenges with regard to blood-brain barrier (BBB) permeability, prompting extensive research interest. This study used a composite emulsification method combined with response surface methodology to optimize the formulation and preparation process, resulting in the design of lactoferrin (Lf)-modified lipid nanoparticles (LNPs)-NMN-LNPs-Lf. LNPs prepared under optimal conditions exhibited spherical morphology with an average particle size of approximately 147 nm, achieving a drug loading capacity of 5.02%, and a Lf modification rate of 41.8%. Using the mouse brain endothelial cell line 3 (bEnd.3) experimental results demonstrated that NMN-LNPs-Lf significantly enhanced NMN's BBB permeability without inducing notable cytotoxicity, achieving a BBB permeability rate of 62%. This permeability was markedly higher than that of conventional unmodified NMN-LNPs and NMN active pharmaceutical ingredients (P < 0.01). NMN-LNPs-Lf significantly altered the pharmacokinetic and tissue distribution in rats. Under identical dosing regimens, the ${\text{AUC}}_{\left(0-\infty \right)}$ , Vz/F, CLz/F, C_max, and ${\text{MRT}}_{\left(0-\infty \right)}$ were significantly higher than API (P < 0.01), accompanied by selective NMN enrichment in brain tissue. Overall, NMN-LNPs-Lf demonstrated an enhanced capacity for brain-targeting delivery in both in vitro cell models and normal rats, suggesting its potential as a therapeutic strategy for neurodegenerative diseases. Future research should incorporate pathological models to conduct in-depth functional and mechanistic evaluations.