ROS-responsive nano-medicine for navigating autophagy to enhance targeted therapy of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder characterized by immune dysregulation and intestinal inflammation. Rapamycin (Ra), an mTORC1 pathway inhibitor, has shown promise for autophagy induction in IBD therapy but is associated with off-target effects and toxicity. To address these issues, we developed an oral liposome responsive to reactive oxygen species (ROS) using lipids and amphiphilic materials. We combined ketone thiol (TK) for ROS responsive and hyaluronic acid (HA) with high affinity for CD44 receptors to prepare rapamycin-loaded nanoparticle (Ra@TH). Owing to its ROS responsive characteristic, Ra@TH can achieve inflammatory colonic targeting. Additionally, Ra@TH can induce autophagy by inhibiting the mTORC1 pathway, leading to the clearance of damaged organelles, pathogenic microorganisms and oxidative stress products. Simultaneously, it also collaboratively inhibits the NF-κB pathway suppressed by the removal of ROS resulting from TK cleavage, thereby mediating the expression of inflammatory factors. Furthermore, Ra@TH enhances the expression of typical tight junction proteins, synergistically restoring intestinal barrier function. Our research not only expands the understanding of autophagy in IBD treatment but also introduces a promising therapeutic approach for IBD patients.