Excessive
reactive oxygen species (ROS) and stressed inflammatory response are major characteristics of
ulcerative colitis, which cause
disease progression and aggravation. Herein, a novel mesoporous
cerium oxide nanozymes (MCN) was designed and then loaded with Myeloid differentiation factor-88 (MyD88) inhibitor for synergistic treatment of
colitis by scavenging ROS and regulating
inflammation. This innovative MCN with average particle size of 200.7 nm, specific surface area of 119.78 m2/g and mesopores of 4.47 nm not only exhibited excellent SOD-like and CAT-like activities to scavenge ROS but also could act as a carrier to load MyD88 inhibitor,
TJ-M2010-5, (abbreviated as TJ-5) into their mesopores, achieving the effect of 'two birds with one stone'. Besides, the modification of
dextran sulfate sodium (TJ-5/MCN/DSS) increased the internalization of nanozymes into activated macrophages and enhanced in vitro anti-inflammatory ability. To enhance colon targeting, we coated TJ-5/MCN/DSS with the enteric material
Eudragit S100, preventing premature release or absorption of the
drug in the gastrointestinal tract after
oral administration. The results demonstrated that TJ-5/MCN/DSS/
Eudragit not only achieved delayed drug release and improved colon targeting but also exhibited optimal therapeutic efficacy in
colitis mice. Mechanistically, the MCN-mediated ROS scavenging and TJ-5-mediated MyD88 blockade synergistically inhibited the NF-κB signaling pathway, thereby reducing the inflammatory response. Importantly, TJ-5/MCN/DSS/
Eudragit did not induce systemic toxicity. In conclusion, our work not only presents a novel carrier capable of scavenging ROS but also provides proof of concept for the synergistic treatment of
colitis using this carrier in combination with MyD88 inhibitors. This study proposes a safe and efficient strategy for targeting ROS-associated
inflammation.