Jiayi Qin, Ke Jiang, Zhining Yuan, Ling Zhang, Banglin Chen
The treatment of infected wounds is severely hampered by the dual challenges of antimicrobial resistance (AMR) and a dysregulated immune microenvironment. Here, we report a hierarchically engineered microreactor (SK@hZnO@ZIF-8, SZZ) that confronts both issues through a synergistic strategy. The reactor’s core design lies in its pH-responsive, nanostructured ZIF-8 shell, which functions as a nanoscale gate for the on-demand release of Shikonin (SK) and Zn 2+ exclusively within acidic infection sites. This stimuli-responsive delivery eradicates over 99.9% of Methicillin-resistant Staphylococcus aureus (MRSA) and, critically, circumvents drug resistance, maintaining >95% efficacy over 20 passages. Beyond its bactericidal action, SZZ actively reprograms the host immune response, orchestrating a shift from a pro-inflammatory to a pro-reparative state by promoting M2 macrophage polarization and upregulating anti-inflammatory cytokines (TGF-β, IL-10). This synergistic bactericidal and immunomodulatory activity translates to effective in vivo efficacy, achieving complete infection clearance and tissue regeneration (including 72.4% collagen deposition and enhanced hair follicle formation) within just 7 days. This work presents a therapeutic paradigm where nanoscale gating mechanisms on a microscale platform are harnessed to resolve infection and orchestrate complex biological repair processes.