Core‐Shell Microneedles for Sequential Delivery of Antibacterial, Antioxidant, and Anti‐Inflammatory Agents in Infected Wound Healing

ABSTRACT

Infected wounds are dynamic pathological processes that progress through acute, chronic, and repair phases, each with distinct therapeutic requirements. Conventional treatments, which release all drugs simultaneously, often fail to meet these stage‐specific needs. In this study, we develop a multifunctional core‐shell microneedle (MN) system capable of sequential delivery of different therapeutics to address the requirements of various healing stages. During the acute phase, the shell composed of gelatin‐hydroxyphenylalanine (Gtn‐HPA) hydrogel rapidly releases bacitracin (Bac), thereby inhibiting bacterial proliferation. During the chronic phase, MMP9‐responsive peptide nanoparticles (INM‐1@EDA) within the MN core undergo enzymatic cleavage, releasing the edaravone (EDA) and indomethacin (INM) moieties to exert antioxidant and anti‐inflammatory activities, respectively. During the repair phase, the residual gelatin at the site supports keratinocyte proliferation and migration, promoting skin tissue regeneration. In a mouse wound model with Staphylococcus aureus infection, core‐shell MN treatment achieves nearly complete wound closure in 12 days (96.7 ± 1.3%) with markedly reduced bacterial burden and decreased inflammatory cytokine levels. This MN system achieves sequential release of antibacterial, anti‐inflammatory, and antioxidant therapeutics based on wound microenvironments, offering new strategies for efficacious treatment of infected wounds.