Carrier-free supramolecular architectonics of quercetin–berberine for safety-redefined therapy of ulcerative colitis

Ulcerative colitis (UC) poses significant clinical management challenges due to the limited efficacy and substantial safety burdens of existing treatments. This study develops a carrier-free supramolecular nanoassembly (QB) composed solely of quercetin (QU) and berberine (BBR), reshaping the safety-efficacy profile of these natural drugs at the nanoscale. Spectroscopic characterization and molecular dynamics simulations reveal that QU and BBR synergistically self-assemble into stable nanoparticles driven primarily by hydrogen bonding and π–π stacking, resulting in a highly negative surface charge and superior colloidal stability. In vitro and in vivo experiments demonstrate that QB markedly reduces BBR's cytotoxicity, expanding its therapeutic dose window by approximately 16-fold, while concurrently enhancing anti-inflammatory, antioxidant, and epithelial barrier repair effects in LPS-stimulated macrophages and DSS-induced UC mice. In vivo fluorescence imaging and tissue distribution indicate selective accumulation of orally administered QB in the inflamed colon and spleen, suggesting dual local intestinal and systemic immune modulatory capabilities. Transcriptomic and gut microbiome analyses further uncover QB's coordinated downregulation of inflammation-related signaling pathways, upregulation of metabolic and antioxidant modules, and restoration of microbial diversity and community homeostasis. Compared to QU or BBR monotherapy and 5-aminosalicylic acid, QB exhibits superior overall efficacy in alleviating colitis symptoms and tissue damage, with excellent biocompatibility, offering a scalable platform for safety-redefined, multidimensional precision interventions in UC based on natural small-molecule self-assembly. • Carrier-free QU–BBR supramolecular nanoassembly remodels UC therapy paradigm. • Self-assembly expands BBR's therapeutic window ∼16-fold while reducing cytotoxicity. • QB selectively accumulates in inflamed colon and spleen via charge-guided targeting. • Multi-omics shows QB modulates inflammation, redox balance, barrier and microbiota. • QB surpasses QU, BBR and 5-ASA in UC remission with excellent biocompatibility.