Reactive Oxygen Species-Responsive Polymer Drug Delivery System Targeted Oxidative Stressed Colon Cells to Ameliorate Colitis

Ulcerative colitis (UC) is a chronic inflammatory condition that imposes a huge healthcare burden globally. The inflamed colon is marked by an abundance of positively charged proteins, increased reactive oxygen species (ROS), a disrupted intestinal barrier, and an imbalanced gut microbiome. Leveraging these features, we designed a negatively charged ROS-responsive nanocarrier using diselenide-bond-modified carboxymethyl cellulose (CMC) for the targeted delivery of curcumin, a natural ROS-scavenging antioxidant, to treat UC. The design rationale encompasses three key aspects: (1) the biocompatible and biodegradable CMC matrix stabilizes curcumin during digestion; (2) the diselenide bonds enable redox-triggered curcumin release at inflammatory sites, ensuring precise therapeutic action; and (3) the negative charge of the nanoparticles enhances interactions with positively charged proteins in inflamed colon tissues, improving site-specific accumulation. Experimental validation confirmed these design principles, demonstrating that the resulting nanoparticles effectively preserve curcumin during digestion and enable the ROS-responsive release of curcumin at inflamed sites. Additionally, these nanoparticles interact effectively with folic acid receptors (positively charged proteins) that are overexpressed on oxidatively stressed cell membranes, leading to specific accumulation in colitis tissue. Subsequently, the nanoparticles scavenge excessive ROS, restore intestinal barrier function, and modulate the gut microbiota. These synergistic actions collectively contribute to significant mitigation of colitis symptoms in both preventive and therapeutic regimens, suggesting a promising alternative therapeutic approach for UC.