OBJECTIVES: This study sought to develop a novel targeted delivery therapy to ablate the major atrial ganglionated plexi (GP) using magnetic nanoparticles carrying a CaCl payload. BACKGROUND: Prior studies indicated the role of hyperactivity of the cardiac autonomic nervous system in the genesis of atrial fibrillation. METHODS: Twenty-eight male mongrel dogs underwent a bilateral thoracotomy. CaCl-encapsulated magnetic nanoparticles (Ca-MNP) included magnetite in a sphere of biocompatible, biodegradable poly(lactic-co-glycolic acid). A custom external electromagnet focusing the magnetic field gradient (2,600 G) on the epicardial surface of the targeted GP was used to pull Ca-MNP into and release CaCl within the GP. The ventricular rate slowing response to high frequency stimulation (20 Hz, 0.1 ms) of the GP was used to assess the GP function. RESULTS: The minimal effective concentration of CaCl to inhibit the GP function was 0.5 mmol/l. Three weeks after CaCl (0.5 mmol/l, n = 18 GP) or saline (n = 18 GP) microinjection into GP, the increased GP function, neural activity, and atrial fibrillation inducibility, as well as shortened effective refractory period in response to 6 h of rapid atrial pacing (1,200 beats/min) were suppressed by CaCl microinjection. After intracoronary infusion of Ca-MNP, the external electromagnet pulled Ca-MNP to the targeted GP and suppressed the GP function (n = 6 GP) within 15 min. CONCLUSIONS: Ca-MNP can be magnetically targeted to suppress GP function by calcium-mediated neurotoxicity. This novel approach may be used to treat arrhythmias related to hyperactivity of the cardiac autonomic nervous system, such as early stage of atrial fibrillation, with minimal myocardial injury.