ANP-GBSA@CHI/TA: A Gut-Targeted Nanomedicine for Attenuating Neuroinflammation and Cognitive Dysfunction

Systemic inflammation has been increasingly acknowledged as a pivotal factor contributing to neuropsychiatric disorders; however, therapeutic approaches specifically targeting neuroimmune interactions remain scarce. Atrial natriuretic peptide (ANP) exhibits strong anti-inflammatory effects but is limited by poor bioavailability and rapid enzymatic degradation. In this study, we developed an orally administered, gut-targeted armored nanomedicine, designated ANP-GBSA@CHI/TA, consisting of ANP-loaded albumin nanoparticles coated with graphene quantum dots and encapsulated within a multilayer shell of chitosan and tannic acid. Comprehensive physicochemical characterization confirmed the successful synthesis of core–shell nanoparticles with an average diameter of 246.8 ± 30.0 nm, demonstrating high encapsulation efficiency, excellent colloidal stability, and significant antioxidant activity, primarily attributable to the nanocarrier components. This formulation enhances intestinal retention and enables targeted delivery to inflamed tissues, as evidenced by in vivo imaging studies. In a lipopolysaccharide (LPS)-induced model of systemic inflammation model, administration of ANP-GBSA@CHI/TA markedly improved cognitive function in behavioral assays, decreased plasma concentrations of pro-inflammatory cytokines (IL-6, TNF-α), and attenuated microglial activation within the hippocampus. Mechanistic investigations revealed that the vagus nerve is indispensable for mediating these therapeutic effects, as subdiaphragmatic vagotomy abolished both the anti-inflammatory and cognitive benefits. Moreover, we demonstrated that ANP-GBSA@CHI/TA enhances hippocampal brain-derived neurotrophic factor (BDNF)/TrkB signaling, and pharmacological inhibition of this pathway significantly reverses the observed cognitive improvements and anti-inflammatory responses, highlighting its critical role in mediating treatment efficacy. Collectively, these findings indicate that this nanoplatform effectively attenuates neuroinflammation and mitigates cognitive deficits via vagus nerve-mediated modulation of the gut–brain axis immune response, thereby representing a promising therapeutic strategy for neuroinflammatory disorders.