Dynamic microenvironment-regulated hydrogels releasing celastrol lead to urethral scarless repair.

The dynamic pathological microenvironment formed post-urethral injury drives an inflammatory-fibrotic cascade, leading to urethral stricture. Herein, we designed a novel hydrogel dressing (CPT-Cel) to modulate this dynamic urethral microenvironment for scarless reconstruction. The hydrogel responsively degrades and releases its contents upon encountering acidic environments and ROS bursts, interrupting the severe oxidative stress-inflammation cycle and creating a favorable regenerative microenvironment in the early wound phase. The incorporated celastrol continuously releases into the late repair phase, inhibiting the hyperactivation of urethral fibroblasts via the TGF-β/NF-κB pathway in urethral microenviroment, thereby preventing excessive collagen secretion. Furthermore, the dressing, featuring an ECM-mimicking microstructure, effectively adheres to and integrates with the injury site, providing hemostatic and antibacterial functions. In animal models of urethral injury, CPT-Cel accelerated urethral repair within the inflammatory milieu, significantly reduced collagen deposition and ultimately improved stricture outcomes. This study not only validates the core mechanism by which an intelligent drug-loaded hydrogel modulates the dynamic urethral microenvironment but also proposes a new paradigm for urethral tissue engineering.