Payload-free protein nanoparticles target inflamed colons to restore intestinal barrier integrity for effectively treating inflammatory bowel diseases

Anti-inflammatory compounds,delivered as a payload to the gastrointestinal tract(GIT)by carriers,still cannot treat inflammatory bowel diseases without avoid-ing side effects.Here,we developed payload-free protein nanoparticles(PNPs)that crossed GIT to retain in the colon and treat colitis by restoring intestinal bar-rier integrity by modulating gut microbiome and metabolome.Specifically,PNPs,orally administered to mice with acute colitis,reached the colon within three hours.Consequently,PNPs improve gut microbiota dysbiosis to reverse metabolism bal-ance,suppressing the expression of tumor-necrosis factorαand toll-like receptor 4 that restores the intestinal barrier integrity.PNPs then ameliorated colon inflam-mation and attenuated gut microbiota dysbiosis by exerting probiotic effects on gut microbiota,treating colitis in a week more effectively than the clinically often used 5-aminosalicylic acid without causing undesired side effects.Such PNPs repre-sent safe,sustainable,and cost-effective therapeutics for treating inflammatory and metabolic diseases by eliminating microbial and metabolomic imbalance.