Natural Antioxidant Lipoic Acid Constructed Nanodrug for Oral Therapy of Inflammatory Bowel Disease

Although antioxidant therapy is promising for inflammatory bowel disease (IBD), the current drugs, such as natural antioxidants and metal nanozymes, cannot meet the needs of efficacy and/or long-term or even lifelong safe administration. Herein, we developed a safe and efficient nanodrug for IBD through self-polymerization of the natural antioxidant lipoic acid (LA) into cross-linked poly(lipoic acid) particles (cLAPs). Owing to the structural homology with the LA monomer, the cLAPs exhibited exceptional biosafety. Orally administered cLAPs selectively adhered to positively charged inflammatory sites in the colon of IBD mice via their negatively charged surface, with a retention time exceeding 36 h. Following polydisulfide-mediated cellular uptake, cLAPs underwent glutathione-triggered depolymerization. This process enabled sustained LA release and prolonged intracellular retention (>6 h) for continuous reactive oxygen species (ROS) scavenging, and ultimately alleviated intestinal inflammation, restored the mucosal barrier, and rebalanced the gut microbiota. In vivo results demonstrated that cLAPs mediated a 75.9% recovery of body weight and a 94.4% recovery of colon length in IBD mice, representing 1.4-fold and 1.6-fold greater efficacy than that achieved by a 5-fold higher dose of sulfasalazine (53.3% and 58.3%, respectively). The natural antioxidant-based nanodrug holds potential in clinic.