Nanoencapsulation modulates aspartame metabolite exposure: Toxicokinetic, mechanistic, and pharmacological evaluation...

Aspartame is a widely consumed artificial sweetener that undergoes rapid metabolic conversion to phenylalanine, aspartic acid, and methanol, metabolites that may contribute to oxidative stress and inflammatory responses under conditions of metabolic vulnerability. This study evaluated whether nanoencapsulation using chitosan nanoparticles could modulate systemic metabolite exposure and attenuate metabolite-associated biological stress responses. Aspartame-loaded chitosan nanoparticles (Asp@CS-NPs) were prepared by ionic gelation and characterized for physicochemical properties, release kinetics, and pharmacokinetic behavior. Nanoencapsulation produced sustained release profiles and significantly reduced peak plasma concentrations (C_max) and systemic exposure (AUC) of phenylalanine compared with free aspartame, indicating altered toxicokinetic behavior. In a glucocorticoid-induced metabolic dysfunction and osteoporosis rat model, reduced metabolite exposure was associated with attenuation of oxidative stress biomarkers, suppression of pro-inflammatory cytokines, preservation of hepatic and renal function, and improvement in metabolic and skeletal endpoints. These effects were accompanied by normalization of redox-sensitive signaling markers, suggesting mitigation of metabolite-induced oxidative and inflammatory cascades. Collectively, the findings indicate that nanoencapsulation can influence toxicokinetic parameters and downstream toxicodynamic responses associated with metabolite exposure. This approach provides a framework for toxicokinetic modulation, whereby controlled absorption reduces peak metabolite exposure and downstream stress responses without altering the intrinsic properties of the parent compound.