A Hierarchical Hydrogel Modulates Immune-Mechanical Microenvironments to Spatiotemporally Reprogram Fibroblasts for...

Fibrosis remains a major challenge in wound repair due to the dual role of fibroblast in tissue regeneration and fibrotic deposition. Early fibroblast activation supports wound closure, whereas sustained activation during remodeling drives fibrosis, making precise temporal regulation a key challenge in advanced wound repair biomaterials design. Herein, a hierarchical hydrogel (CC-pMnO₂-Vet@PNAA) was engineered to spatiotemporally regulate fibroblast behavior, achieving fibrosis suppression without compromising wound healing rate. The hydrogel matrix was constructed by reversibly reassembling irregular thermo-responsive PNAA microgels (LCST∼45°C) with caffeic acid (CA)-modified chitosan (CS-CA) via dynamic boronate ester linkages. Based on a hierarchical physical encapsulation architecture, CC-pMnO₂-Vet@PNAA enabled the highly controllable, stage-specific release of polydopamine-modified MnO₂ (pMnO₂) and verteporfin nanoparticles (Vet NPs). During the early inflammatory phase, the hydrogel rapidly disassembled in response to pathological cues (low pH, high ROS), releasing pMnO₂ and CS-CA to synergistically eliminate bacteria (>99%), neutralize oxidative stress, and restore immune homeostasis. Subsequently, in the remodeling phase, localized near-infrared (NIR) irradiation triggered microgel contraction for the on-demand release of Vet NPs, suppressing YAP signaling in fibroblasts to rebalance the mechanical microenvironment. In vivo studies in diabetic Sprague-Dawley (SD) rats model demonstrated that CC-pMnO₂-Vet@PNAA established a coordinated immune-mechanical microenvironment, achieving rapid and scar-free wound healing.