An In Situ Transformable Orally Administrated System for Targeted Intestinal Barrier Protection and Inflammatory Microenvironment Modulation in Sepsis Therapy

Abstract Sepsis is a life‐threatening condition characterized by organ dysfunction caused by a dysregulated host response to infection. An inflammatory intestinal environment, disruption of the intestinal epithelial barrier, impairment of the mucus layer, and dysregulation of the gut microbiome can lead to pathogen translocation and increased susceptibility to sepsis. Hence, an orally administered nanomedicine is developed, S‐Z@M nanoparticles (NPs), based on food‐derived mussel adhesive protein (M)‐modified zeolitic imidazolate framework‐8 (Z) for the targeted delivery of anti‐inflammatory herbal medicine. S‐Z@M NPs exert multi‐therapeutic effects by forming a physical barrier at injured intestinal sites and persistently activating anti‐inflammatory pathways. First, S‐Z@M NPs scavenge reactive oxygen species (ROS) to reduce oxidative stress injury. After ROS‐triggered charge transition and oxidative cross‐linking, the M layer adheres to the negatively charged damaged mucosa to form a physical barrier, preventing further damage from microorganisms and toxins. Sinomenine (S) releases from Z NPs in response to an acidic environment suppresses pro‐inflammatory pathways, thereby inhibiting intestinal epithelial cell apoptosis and restoring intestinal tight junctions and gut microbiota homeostasis. Overall, S‐Z@M NPs show a strong potential to regulate the inflammatory microenvironment and restore intestinal barrier function, opening the door for further exploitation in sepsis therapy.