Natural Carrier-Free Self-Assembled Binary Polyphenol Nanoparticles Remodel the Gut Microenvironment for Inflammatory Bowel Disease Prevention

Developing biocompatible, multi-target therapeutics remains a critical challenge in the management of inflammatory bowel disease (IBD). Herein, we engineered a carrier-free nanoplatform (Cur-Ant NPs) via the facile self-assembly of two natural polyphenols: curcumin (Cur) and anthocyanin (Ant). Spectroscopic analysis and molecular dynamics simulations confirmed that the assembly is stabilized by robust π-π stacking and hydrogen bonding networks, yielding uniform, spherical nanostructures with integrated functionality. In a dextran sulfate sodium (DSS)-induced colitis model, orally administered Cur-Ant NPs demonstrated superior therapeutic efficacy compared to both free polyphenols and the clinical standard, sulfasalazine (SASP). The nanoparticles' potent anti-inflammatory activity was initially validated in a zebrafish model, where they effectively inhibited neutrophil infiltration and scavenged reactive oxygen species (ROS). These protective effects were further substantiated in a murine model, where multi-omics analysis revealed a tripartite mechanism of action: reinforcing the intestinal epithelial barrier, mitigating pro-inflammatory cytokine responses, and remodeling the dysbiotic gut microbiome. Our findings establish Cur-Ant NPs as a potent, safe candidate for IBD prevention and highlight a scalable, green engineering strategy for designing next-generation nanomedicines based on the supramolecular co-assembly of natural bioactive agents. • Carrier-free nanomedicine engineered via green supramolecular self-assembly of binary natural polyphenols. • Molecular dynamics simulations and spectral analysis elucidate the assembly mechanism driven by π-π stacking and H-bonding. • Cur-Ant NPs demonstrate superior colonic accumulation and therapeutic efficacy over sulfasalazine in colitis models. • The nanoplatform synergistically remodels the gut microenvironment by scavenging ROS, restoring barrier integrity, and reversing dysbiosis.