Nitric oxide-entrapping bio-adhesive coacervate foam for multi-target therapy of gastrointestinal infections.

Bacterial biofilms and persistent inflammation undermine conventional antibiotic therapy for gastrointestinal infections, necessitating integrated therapeutic strategies. Here, we develop a nitric oxide (NO)-entrapping coacervate foam (LA-CHSF-NO) from α-lipoic acid-grafted chitosan and sodium alginate that synergistically combines antimicrobial, antioxidant, anti-inflammatory, and mucosal-healing functions. The foam exhibits robust mechanical properties (storage modulus ∼1184 Pa), shear-thinning injectability, self-healing capacity, and sustained NO release over 4 h, enabling durable mucosal retention. LA-CHSF-NO achieves potent bactericidal and anti-biofilm activity against E. coli, MRSA, and P. aeruginosa (>85% eradication) through synergistic membrane disruption and NO-mediated nitrosative stress. Mechanistically, the foam scavenges ROS, activates the Keap1-Nrf2-HO-1 antioxidant axis, promotes macrophage M2 polarization, and suppresses TNF-α, IL-6, and IL-1β while restoring IL-10. In DSS-induced colitis, LA-CHSF-NO alleviates disease severity, repairs epithelial barrier via upregulating occludin, ZO-1, and claudin-5, restores antioxidant enzymes, and normalizes gut microbiota. Remarkably, in H. pylori-induced gastritis, oral LA-CHSF-NO achieves superior bacterial clearance and mucosal healing versus standard triple therapy. This gas-delivery platform offers a paradigm-shifting approach for combating antibiotic-resistant gastrointestinal infections and chronic inflammatory diseases.