Carnosic acid-loaded stimuli-responsive hydrogel promotes wound healing through PGP-1 mediated immune remodeling

Persistent inflammation is a major barrier to effective wound healing. The local immune microenvironment, closely associated with the inflammatory state, exerts central regulatory control throughout repair. Pyroglutamyl aminopeptidase 1 (PGP-1) is implicated in inflammation-related conditions, but its role in wound inflammation and regeneration remains unclear. Here, carnosic acid (CA) was identified as a potent PGP-1 inhibitor that reduced the production of pro-inflammatory cytokines and promoted M2 macrophage polarization, thereby demonstrating substantial potential to remodel the immune microenvironment. Based on this, CA was employed as a bioactive structural building block, together with 4-aminophenylboronic acid (APBA), to construct a stimuli-responsive hydrogel (CAP hydrogel). The hydrogel not only exhibited self-healing ability and cytocompatibility (cell viability ~95%), but also achieved 82.48% of pH/ROS-responsive CA release, with accelerated release under acidic and ROS-rich conditions that mimic inflammatory wounds. This targeted responsiveness is expected to enhance on-demand local CA availability during the early inflammatory phase, thereby strengthening PGP-1 inhibition and immune microenvironment remodeling. In the deep burn wound model, the CAP hydrogel significantly accelerated wound closure and improved angiogenesis after 20 days of treatment. In addition, it promoted favorable remodeling of the local immune microenvironment by downregulating PGP-1 and related inflammatory signaling pathways. Overall, this study provides a feasible strategy for promoting wound healing through PGP-1 inhibition and immune microenvironment modulation. It also presents a functional hydrogel with translational potential for advanced wound care and regenerative medicine.