Covalently Conjugated Synergistic Antibacterial–Antioxidant Polylactic Acid Nanofiber Membranes for Chronic Infected Wound Healing

Chronic infected wounds remain challenging to treat, primarily due to persistent bacterial infection and dysregulated inflammation. Conventional dressings with physically blended bioactives suffer from burst release and unstable retention. Herein, curcumin (Cur) and a dihydroxy-quaternary ammonium salt (Qas) were covalently linked to polylactic acid (PLA) (forming PCur and PQas). This strategy eliminated burst release, enabling sustained bioactive release for 21 days (vs <72 h for physical blends P/Cur, P/Qas). <i>In vitro</i>, PCur showed enhanced antioxidant activity, while PQas demonstrated stronger bacterial inhibition. <i>In vivo</i>, the covalently modified membranes promoted 97.8% wound closure by day 14, with PCur reducing TNF-α and PQas suppressing bacterial rebound. The functional order (PCur > PQas > physical blends > PLA) underscores the critical role of covalent conjugation in balancing antimicrobial, antioxidant, and regenerative functions for prolonged wound therapy. Covalent conjugation is key for balanced functions, offering a sustained therapy for chronically infected wounds.