An In Situ Self-Solidifying Poly(Lipoic-Acid) Liquid Adhesive Forms Pathogen-Resistant Barrier for Ulcerative Colitis Therapy

Ulcerative colitis (UC), a refractory inflammatory bowel disease, features exacerbated inflammation, barrier disruption, and microbiota dysbiosis. While nanodrug delivery is a prevalent therapeutic strategy, it faces severe limitations, including inadequate targeting, poor mucus penetration, lysosomal entrapment, reducing bioavailability, and a lack of barrier repair capability. To overcome these limitations, an in situ self-solidifying mucus-mimetic poly(lipoic-acid) liquid adhesive (PLALA) is engineered via a biobenign aqueous assembly route. The rod-shaped sodium lipoate (LANa) micelles spontaneously formed in water and relying on a reasonable amphipathic structure, solubilize lipoic acid (LA) via palisade-layer incorporation, and undergo concentration-induced ring-opening polymerization and hydrogen-bond-driven self-assembly. The resulting moisture-responsive PLALA adheres selectively to inflamed mucosa via electrostatic targeting, achieving conformal mucosal coverage up to micron-scale rugae. The PLALA solidifies in situ under intestinal fluid-induced hydrophobic aggregation, forming a durable, pathogen-resistant barrier while releasing anisotropic lipoic-based nanomicelles. These high-aspect-ratio micelles penetrate the mucus layer efficiently and facilitate direct cytosolic delivery into intestinal epithelial cells via thiol-disulfide exchange, evading lysosomal degradation to enhance antioxidant efficacy and inhibit apoptosis. In rat UC models, the PLALA demonstrates synergistic therapeutic efficacy by restoring epithelial barriers, suppressing inflammation, and remodeling microbiota─all without use of exogenous drugs, offering a paradigm-shifting strategy for UC therapy.