Novel Natural Carrier‐Free Self‐Assembled Nanoparticles for Treatment of Ulcerative Colitis by Balancing Immune Microenvironment and Intestinal Barrier

Ulcerative colitis (UC) is a chronic inflammatory illness affecting the colon and rectum, with current treatment methods being unable to meet the clinical needs of ulcerative colitis patients. Although nanomedicines are recognized as promising anti‐inflammatory medicines, their clinical application is limited by their high cost and unpredictable safety risks. This study reveals that two natural phytochemicals, berberine (BBR) and hesperetin (HST), self‐assemble directly to form binary carrier‐free multi‐functional spherical nanoparticles (BBR‐HST NPs) through noncovalent bonds involving electrostatic interactions, π–π stacking, and hydrogen bonding. Because of their synergistic anti‐inflammatory activity, berberine–hesperetin nanoparticles (BBR‐HST NPs) exhibit significantly better therapeutic effects on UC and inhibitory effects on inflammation than BBR and HST at the same dose by regulating the immune microenvironment and repairing the damaged intestinal barrier. Furthermore, BBR‐HST NPs exhibit good biocompatibility and biosafety. Thus, this study proves the potential of novel natural anti‐inflammatory nanoparticles as therapeutic agents for UC, which could promote the progress of drug development for UC and eventually benefit patients who suffering from it. This study introduces berberine and hesperetin nanoparticles (BBR‐HST NPs), binary carrier‐free self‐assembly nanoparticles, as a potential treatment for ulcerative colitis. Demonstrating efficacy in dextran sodium sulfate (DSS)‐induced colitis mice, BBR‐HST NPs also restore the intestinal barrier, microbiota, and immune system. This research offers a promising ulcerative colitis treatment and advances carrier‐free nanodrug development.