Oral Magnetoelectric Neuroimmunomodulation via the Gut–Brain–Spleen–Heart Axis for Noninvasive Atrial Fibrillation Therapy

Atrial fibrillation (AF), the most common cardiac arrhythmia, is closely associated with autonomic imbalance and inflammation. While low-level vagus nerve stimulation (LL-VNS) offers therapeutic benefits, its clinical application is limited by the need for surgical implants. Here, we present a noninvasive, orally delivered magnetoelectric neuroimmunomodulation platform that targets the gut-brain-spleen-heart axis to deliver LL-VNS for AF therapy. The platform comprises ingestible microparticles (MPs) embedding magnetostrictive Fe₃O₄@BaTiO₃ nanogenerators (FO@BTO NGs) within a conductive matrix of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), which facilitates electrical signal transmission, and dopamine-alginate, which promotes gastric adhesion via catechol-mediated interactions. After oral gavage in a rat AF model, MPs adhere to the stomach lining and, upon alternating magnetic activation, FO@BTO NGs generate pulsed electrical currents that stimulate vagal afferent fibers. This activates brainstem autonomic circuits, enhancing parasympathetic tone and suppressing sympathetic activity. Concurrently, it engages the splenic neuroimmune circuit via the cholinergic anti-inflammatory pathway, thereby reducing systemic inflammation. This dual neuroimmune modulation significantly shortens AF duration and mitigates cardiac inflammation and electrical remodeling. These findings establish a clinically translatable, implant-free strategy for delivering LL-VNS through coordinated neural and immune pathways, offering a safe and accessible alternative to implantable systems for AF management.