A Dual pH‑Responsive Hydrogel with Site‑Specific Therapeutic Functions for Differential Pathological Microenvironment Remodeling and Accelerated Repair of Infected Diabetic Wounds

Abstract Diabetic skin wounds have disrupted local acid–base balance, prone to bacterial adhesion and sustained chronic inflammation that hinders tissue repair. Benefiting from the unique properties of oxidized sodium alginate, we prepared a dual pH-responsive Schiff base crosslinked hydrogel loaded with herbal nanoparticles to remodel the defective wound microenvironment and speed up regeneration. Dynamic covalent crosslinking endows the hydrogel with favorable flexibility and shape adaptability to fit irregular wound surfaces. It exhibits obvious dual pH sensitivity: strong antibacterial activity in bacteria-rich acidic niches and slow hydrolysis under diabetic wound alkalinity, achieving stable drug release without burst leakage. The encapsulated nanoparticles exhibit multiple complementary functions. Zn2+ acts as an efficient bactericide to eliminate pathogens. L-Arginine facilitates nitric oxide (NO) generation to promote angiogenesis and M2 macrophage polarization. The glycyrrhetinic acid-2-hydroxyacetophenone conjugate (GA-HAP) suppresses proinflammatory cytokines to relieve local inflammation. In vitro and in vivo experiments verify that this composite hydrogel balances wound pH, eradicates bacterial infection, and mitigates persistent inflammation, remarkably accelerating diabetic wound healing. This pH-sensitive herbal hydrogel holds great potential for microenvironment regulation and clinical therapy of intractable diabetic wounds.