A groundbreaking discovery in modernizing traditional Chinese medicine (TCM) has been achieved. A study has, for the first time, confirmed that stable, naturally occurring nanoparticles with intact bioactivity—named Pueraria lobata (GeGen) decoction-derived vesicle-like nanoparticles (GGD-PDVLNs)—exist in the decoction prepared using the traditional boiling method. Experiments have demonstrated that these nanoparticles constitute the core active component responsible for the therapeutic effects of the decoction. They function by reshaping the gut microbiota to treat ulcerative colitis, with efficacy dependent on the microbiota. This finding redefines the scientific understanding of traditional herbal decoctions and establishes a new paradigm for developing natural nanomedicines.