Hyaluronic acid-based reactive oxygen species responsive nanocomposite hydrogel for sequential drug delivery and effective prevention of postoperative abdominal adhesions

Postoperative abdominal adhesion (PAA) affects over 90% of abdominal surgery patients and remains a huge clinical challenge. Sustained inflammation with excessive reactive oxygen species (ROS) production and subsequent peritoneal mesothelial cells (PMCs)-mesenchymal transition (MMT) are key events driving PAA formation. Herein, we engineer a ROS-responsive nanocomposite hydrogel (P/H/PBLA@PFD) for ROS-triggered sequential delivery of antioxidant/anti-inflammatory drugs and MMT inhibitors for effective PAA prevention. P/H/PBLA@PFD hydrogel is fabricated via Schiff base crosslinking between aldehyde-functionalized Pluronic F127 micelles loaded with pirfenidone (PFD) and adipic dihydrazide-modified hyaluronic acid (HA-ADH), concurrently incorporating a ROS-responsive antioxidant dihydrolipoic acid prodrug PBLA which forms a diazaborine (DAB) structure via click chemistry with HA-ADH. P/H/PBLA@PFD displays tissue-mimetic mechanical properties and good tissue adhesion to retain in cecum for at least 7 days. The elevated ROS in wound microenvironment triggers DAB cleavage and the subsequent on-demand antioxidant drug release, enabling cascade ROS elimination to reduce inflammation. Moreover, hydrogel network breakage enlarges its pore size, achieving ROS-triggered sequential sustained release of PFD to inhibit TGF-β1-mediated MMT process of PMCs, finally realizing temporal regulation of the key PAA formation cascade. Ultimately, P/H/PBLA@PFD hydrogel effectively prevents PAA formation in a rat model through coordinated ROS scavenging, anti-inflammatory and fibrosis suppression with good biocompatibility.