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

Abstract Anti‐inflammatory compounds, delivered as a payload to the gastrointestinal tract (GIT) by carriers, still cannot treat inflammatory bowel diseases without avoiding side effects. Here, we developed payload‐free protein nanoparticles (PNPs) that crossed GIT to retain in the colon and treat colitis by restoring intestinal barrier 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 balance, suppressing the expression of tumor‐necrosis factor α and toll‐like receptor 4 that restores the intestinal barrier integrity. PNPs then ameliorated colon inflammation 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 represent safe, sustainable, and cost‐effective therapeutics for treating inflammatory and metabolic diseases by eliminating microbial and metabolomic imbalance.