Intestinal molecular siphoning by engineered bacterial spores for non-systemic treatment of nicotine addiction

Eradicating toxic small molecules from the body typically requires the administrations of therapeutic agents for systemic circulation and tissue distribution, resulting in inevitable adverse events from off-target effects. Here, we propose a intestinal molecular siphoning approach for treating diseases caused by toxic substances, in which enzymatic degradation of a toxic substance in the intestinal lumen serves as a driving force for the diffusion of the toxic substance from blood to gut, and continuous elimination of the toxic substance in the gut could effectively ease substance dependence. Using nicotine as a model substance, a live bacterial system was constructed by displaying a trypsin-resistant nicotine oxidase on the surface of Bacillus subtilis spores, and encapsulating in enteric-coated microspheres for gastric protection and targeted intestinal release. After oral treatments with the live bacterial system in mice, peak concentrations of nicotine in blood and brain were remarkably reduced compared to controls. Moreover, the live bacterial system could effectively attenuate nicotine addiction by suppressing dopamine reward surges to reverse withdrawal hyperalgesia, preventing the upregulation of nicotinic acetylcholine receptors, and alleviating anxiety-like behaviors. These findings show the potential of intestinal molecular siphoning as a target-independent therapeutic strategy for lowering circulating toxic substances through non-systemic enzyme reprogramming.