Self-assembled nanoparticles from Xiexin Decoction attenuate ulcerative colitis by targeting VDAC1-Mediated NLRP3 inflammasome activation.

Ulcerative colitis (UC) remains a clinical challenge due to limited efficacy and side effects of conventional therapies, highlighting the need for novel interventions. Here, we investigate the therapeutic potential of naturally derived self-assembled nanoparticles (XDNPs) from the traditional Chinese medicine formula Xiexin Decoction (XXD) and rationally designed carrier-free nanoparticles (RBNPs) composed of berberine (BBR) and rhein. Both formulations effectively mitigated DSS-induced colitis by normalizing gut dysbiosis, reducing the release of pro-inflammatory mediators and facilitating macrophage phenotypic switching. Mechanistically, activity-based protein profiling identified VDAC1 as a direct functional target of BBR. Binding to VDAC1 inhibits its oligomerization, preventing the cytosolic release of oxidized mitochondrial DNA and subsequent activation of the NLRP3 inflammasome in macrophages. Co-assembly with rhein further enhances cellular uptake and bioavailability, amplifying anti-inflammatory efficacy. Proteomic and molecular analyses confirmed broad modulation of immune and metabolic pathways, while in vivo safety assessments demonstrated excellent biocompatibility without detectable organ toxicity. Collectively, this work elucidates a VDAC1-mediated mechanistic axis underlying the potent therapeutic effects of BBR-containing nanoparticles and establishes a rational nanomedicine strategy inspired by traditional herbal formulations. These findings provide a promising platform for the development of targeted, biocompatible nanotherapeutics for UC and other inflammatory disorders.