Nano-functionalized probiotic treats atherosclerosis via inhibiting intestinal microbiota-TMA-TMAO axis

Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE^-/- mice demonstrate that PDMF@LGG reduces TMAO levels, alleviates atherosclerotic plaque formation, and regulates gut microbial composition and various metabolites. Together, PDMF@LGG represents a potential candidate for atherosclerotic therapy caused by TMAO and broadens the range of treatable atherosclerosis.