Abstract

Rational carrier design for colon-specific delivery The microparticles contain β-sheet–rich silk fibroin matrices for hydrophobic drug encapsulation with a chito-oligosaccharide coating that enables mucoadhesion, enzyme-responsive degradation, and microbiota-triggered colon targeting , effectively minimizing premature release in the upper gastrointestinal tract. • Synergistic drug codelivery with mechanistic validation PA and PT exert synergistic effects by simultaneously suppressing inflammatory cytokines, reducing epithelial apoptosis, and restoring tight junction and mucus barrier integrity , providing a multi-pronged therapeutic strategy. • Robust in vivo efficacy in two clinically relevant disease models Oral administration of SF@COS microparticles significantly outperformed a conventional drug in both DSS-induced colitis and CPT-11–induced chemotherapy colitis , including superior protection against mucosal erosion, goblet cell loss, oxidative stress, and barrier disruption. Refractory colonic lesions, including ulcerative colitis and chemotherapy-induced colitis, represent significant clinical challenges. Patchouli alcohol (PA) and pogostone (PT) are the main pharmacological ingredients of patchouli volatile oil (PO), widely used for treating gastrointestinal tract disorders. PA and PT exhibit promising therapeutic effects on colonic lesions, such as immune-regulation and mucosal barrier repair, but with poor stability and low water solubility. It is a challenge of colon-specific delivery of PA and PT. In this work, we developed a layer-by-layer silk fibroin microparticle system (SF@COS) coated by chito-oligosaccharide. The microparticles exhibited a mean diameter of 3.1 μm and a zeta potential of +8.6 mV. Encapsulation efficiencies reached 80.8% for PA and 74.7% for PT, benefiting from hydrophobic interactions between the amphiphilic SF β-sheet structure and the lipophilic drugs. In addition, chito-oligosaccharide coating on the thus-formed SF micropa