Programmed nanozyme hydrogel enabling spatiotemporal modulation of wound healing achieves skin regeneration after biofilm infection

Skin regeneration after wound healing is challenging, especially following infection. Wound repair is a staged yet continuous program, necessitating distinct therapeutic approaches at each stage. Regulation of infection-induced excessive reactive oxygen species (ROS) represents a strategy. Thus, this study employs a therapeutic program involving ROS-responsive nanozyme release, ROS-generation, and ROS-scavenging to achieve dynamic modulation of wound microenvironment. Furthermore, by leveraging the physicochemical properties of the hydrogel to match healing requirements, both macroscopic and microscopic programmed treatment were achieved. In vitro studies confirmed that the treatment reprograms the infected microenvironment by attenuating lipopolysaccharide (LPS)/ ROS-driven inflammation, promoting M2 macrophage polarization, and suppressing myofibroblast over-activation, establishing coordinated control over "infection-inflammation-fibrosis". In vivo results demonstrated that skin regeneration was achieved through advancing inflammation-to-proliferation phase transition temporally and by spatially guiding the healing direction. To further understand the spatial skin regeneration, a novel analysis named the 'Patch Repair Division Method' was reported to showcase the differences in the spatial structure between scar and regenerative area after the treatment. The altered healing orientation further resulted in more organized dermal architecture, enhanced hair follicle neogenesis, and improved vascularization. Collectively, these effects enabled the biofilm-infected wounds to achieve skin regeneration instead of scar formation.