Succinylated casein-coated peptide-mesoporous silica nanoparticles as an antibiotic against intestinal bacterial infection.

Increasing drug resistance necessitates the discovery of novel bactericides. Human defensin (HD) peptides can eliminate resistant bacteria and are promising candidates for next-generation antibiotics. T7E21R-HD5 is a potent bactericide designed by site mutations at enteric HD5. To facilitate the development of T7E21R-HD5 into an intestinal antibiotic, we employed a mesoporous silica nanoparticle (MSN) as the peptide carrier. Despite its ineffectiveness at killing bacteria, the MSN intensified the outer membrane penetration and inner membrane permeabilization abilities of T7E21R-HD5 and thus enhanced its antibacterial action against multidrug resistant (MDR) E. coli, which broadened the role of MSNs in drug delivery. For the reduction in T7E21R-HD5 losses in the stomach, we further modified MSN@T7E21R-HD5 with succinylated casein (SCN), a milk protein that can be specifically degraded by intestinal protease. SCN coating decreased T7E21R-HD5 release from the MSNs, especially in a highly acidic environment. The controlled release of MSN@T7E21R-HD5 from SCN encapsulation was confirmed in the presence of trypsin. MSN@T7E21R-HD5@SCN was nontoxic to host cells, and it was capable of inactivating MDR E. coli in vivo and alleviating intestinal inflammation by suppressing the production of inflammatory factors TNF-α, IL-1β, and MMP-9. This study provides a peptide-based nanobiotic with efficacy to combat intestinal infection, especially against drug-resistant bacteria. The biocompatible and readily prepared MSN/SCN delivery system may benefit further intestinal antibiotic design and promote the drug transformation of additional enterogenic functional molecules.